Skip to main content

Full text of "Diagnostic tools in Rhinology EAACI position paper."

See other formats

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Clinical and Translational 


Diagnostic tools in Rhinology EAACI position paper 

Glenis Scadding 1 , Peter Hellings 2 , Isam Alobid 3 , Claus Bachert 4 , Wytske Fokkens 5 , Roy Gerth van Wijk 6 , 
Philippe Gevaert 4 , Josep Guilemany 3 , Livije Kalogjera 7 , Valerie Lund 1 , Joaquim Mullol 3 , Giovanni Passalacqua 8 , 
Elina Toskala 9 and Cornelius van Drunen 5 


This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of 
the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the 
different important issues related to history taking, clinical examination and additional investigative tools for 
evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field 
of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology. 


There are several reasons for accurate investigation of 
upper airways disorders like allergic rhinitis [1] and rhi- 
nosinusitis [2]. The first reason relates to the fact that 
such problems impact very significantly upon patients' 
quality of life and that well directed treatment can ame- 
liorate the impairment of quality of life. The second is 
that some of these disorders are severe with significant 
morbidity and even mortality, and that presentation often 
occurs in the upper airway. Early diagnosis and effective 
management can prevent serious consequences, like in 
Wegeners' granulomatosis. The third reason relates to 
the fact that upper respiratory tract problems exacerbate 
lower respiratory symptoms and may extend to involve 
the lower respiratory tract. The nose is an air condi- 
tioner; filtering, warming and humidifying over 10,000 
liters of air daily before it progresses to the lungs. 

The nasal passages and associated structures bear the 
brunt of environmental contact being the first site of 
allergen, microbial and particle deposition. As a conse- 
quence the upper airway is the location of a highly devel- 
oped innate and adaptive immune system. Effective 
mucociliary clearance is vital for respiratory health as evi- 
denced by the effects of defects such as primary ciliary 
dyskinesia (PCD) and cystic fibrosis (CF). Lower airways 
disease is often preceded by nasal and sinus disease lead- 
ing to a window of opportunity for early diagnosis and 
possibly prevention of severe complications. For example 

* Correspondence: 

'Royal National Throat, Nose and Ear Institute, London, UK 

Full list of author information is available at the end of the article 

measurement of nasal nitric oxide is simple and quick 
and very low levels can alert the physician to the possibi- 
lity of PCD before major lung damage is sustained, thus 
allowing the benefit of early physiotherapy. 

Inflammatory airways diseases usually start in the nose. 
This observation does not only hold true for allergic and 
non-allergic rhinitis in older children and adults which 
can progress to asthma, but also for respiratory occupa- 
tional disease, and for rhinosinusitis which can be the pre- 
sentation of Wegener's granulomatosis or Churg Strauss 
syndrome and is also associated with bronchiectasis. 

The ability to recognize and accurately diagnose nasal 
disease should be a part of the armamentarium of all 
allergists, chest physicians and paediatricians as well as 
ENT surgeons. In addition, the nose provides an ideal 
area for investigation of disease mechanisms. It has given 
us insights into the pathogenesis of allergic disease and of 
changes during pharmaco- and immunotherapy. Now 
investigations into other forms of inflammatory and non- 
inflammatory nose and sinus disease are ongoing with 
possibly new forms of therapy as a result. So researchers 
might also find this Position Paper of use. This document 
aims to provide a basic introduction into methods used 
in Rhinology - their applicability, specificity and sensitiv- 
ity. It will hopefully become outdated soon by new 
advances in the field. 

History of the Patient 


The patients' history is vital in understanding and diag- 
nosing the problem. In rhinitis and rhinosinusitis an 

O© 201 1 Scadding et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative 
BiolVlGCl C^ntrBl Commons Att ibution License (http:/A n itive which permits unres cted use, dis ribution, and 
reproduction in any medium, provided the original work is properly cited. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 2 of 39 

accurate history is usually more important than any 
other investigation. 

The aim of any history taken is to evaluate the pre- 
sence, severity and duration of symptoms, aiming at an 
accurate diagnosis and enabling adequate treatment. 


The medical history represents the patients' or a respon- 
sible carers' account of the problem, supplemented by 
direct questioning. 


A one-to- one interview is preferred, with or without 
the aid of a questionnaire with evaluation of the severity 
of the symptoms on a Visual Analogue Scale (VAS). 

In spite of the patients' history being the mainstay of 
clinical diagnosis and therapeutic approach, the history 
and clinical examination in allergic rhinitis may deviate 
considerably from concordant SPT and slgE results [3]. 
Patients' history is however the primary standard used 
in judging test sensitivity and specificity. 
1. Allergic Rhinitis 

Rhinitis is defined as having two of the listed symptoms 
for >1 hour/day for >2 weeks: blockage, running (includ- 
ing postnasal drip), sneezing and itching. Nasal pro- 
blems are often multi-factorial in nature, which needs to 
be taken into account when using the classification or 
considering treatment. 

The diagnosis of allergic rhinitis (AR) is based upon the 
concordance between a typical history of allergic symp- 
toms and diagnostic tests. Typical symptoms of AR 
include rhinorrhoea, sneezing, nasal obstruction and 
pruritus. Depending on the sensitization pattern, patients 
with AR may be predominantly runners and sneezers or 
suffer from chronic obstruction with discharge which is 
mainly post nasal. Ocular symptoms are common, in par- 
ticular in patients allergic to outdoor allergens. Conjunc- 
tivitis is found in 70% of pollen allergic rhinitis patients 
and around half of those with perennial rhinitis. Always 
ask about the following eye symptoms: redness, 
discharge, itching, and vision impairment. Symptoms 
related to reduced smell and taste are more typical of 

Figure 1 highlights the differences between symptoms 
suggestive of AR and those usually not associated with 
AR, and shows the criteria for severity of disease in rela- 
tion to duration and associated extra-nasal symptoms. 
History should include specific symptom-related ques- 
tions like: 

♦ timing of symptoms (intermittent vs persistent dis- 
ease, Figure 1) 

♦ severity of symptoms (mild, moderate or severe, 
Figure 1) 

• provoking factors e.g. animal contact 

• alleviating factors e.g. holiday away from home 

• occupational aggravation e.g. animal care facility 

• seasonal aggravation e.g. grass pollen season 

• effects of treatments tried in the past 

• intolerance to medication e.g. aspirin 

• associated oral allergy symptoms 

Allergy is a more likely diagnosis if there is a past, 
present or family history of allergic diseases (AR, 
asthma, atopic dermatitis). 

Rhinitis symptoms without obvious allergic triggers 
may still be allergic in origin so specific IgE testing is 
advisable for all sufferers. Those with a good history for 
an allergic cause who are negative on specific IgE tests 
in blood or on skin should have the benefit of a nasal 
challenge with the likely allergen since local nasal IgE 
production can occur. 

AR and asthma usually co-exist, with symptoms of 
rhinitis found in 75-80% of patients with asthma and 
asthma in up to a third of rhinitis patients. Therefore 
patients should also be asked about lower respiratory 
tract symptoms (wheeze, cough, dyspnoea, sputum) and 
functional measurements (spirometry, peak flow) made. 

There is an association between rhinitis and OME in 
childhood [4] so questions on hearing, listening, lan- 
guage, learning and behavior should be included in chil- 
dren with rhinitis, and ear examination and hearing 
tests including tympanometry and audiometry per- 
formed if a problem is suspected. Adults rarely develop 
OME unless they have a severe form of rhinosinusitis 
(Churg-Strauss syndrome, aspirin sensitivity, allergic 
fungal sinusitis). 

Pharyngitis/laryngitis- can occur secondary to rhinitis 
or may be the predominant feature. 

Food allergy is often associated with allergic airway 
disease and atopic dermatitis [5], and should therefore 
be asked for during history taking. 

Sleep problems-are common in rhinitis and can be det- 
rimental to quality of life and to work/school perfor- 
mance. Difficulty in going to sleep, snoring, mouth 
breathing at night, waking with a dry or swollen mouth 
and throat, daytime somnolence, headache, ability to 
attend and function at work or school should be queried. 
2. Non- Allergic rhinitis 

In rhinitis patients who are not allergic, i.e. having nega- 
tive skin prick test results or blood analysis for allergen- 
specific IgE, there is an extensive differential diagnosis 
(Figure 2). 

In small children frequent viral upper respiratory tract 
infections occur- between 6 and 8 annually on average. 
Helpful questions include whether symptoms were pre- 
sent from birth (consider primary ciliary dyskinesia 
(PCD) or cystic fibrosis (CF)), and whether they ever 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 3 of 39 

Symptoms suggestive 
of allergic rhinitis 

Symptoms usually NOT associated 
with allergic rhinitis 

2 or more of th« following symptoms for 
> I h on most days 

- watery anterior rhinorrhea 

- sneezing, especially paroxysmal 

- natal obstruction 

- nasal pruritic 
± conjunctivitis 

unilateral symptom* 

■ ncssl obstruction without c-her symptoms 

■ mucopurulent rhinorrhea 

- posterior rhinorrhea (post nasal drip) 

-with thick mucous 
-and/or no anterior rhinorrhea 

- recurrent epistaxi* 

■ anosmia 



1 <4 aays per wee* 

1 or <4 cocsecutive weeks 



• >4 oayv'week. 

• era >4 consecur »r wcoki 


all of the following 

• "Ormal sleep 

• no irrtpo rnent of doily octvries, sport, leisure 

• -o iTpoi'Tert o ; wo-k o-d school 

• symptoms present but not "roubieione 


Moderate - Severe 

one or more items 

• sleep disturocce 

■ TDormrnl o*' do y oc'ivil es. spot*. 

• impairment of vchool o' wort 

• troublesome symptoms 

Figure 1 Symptom-based diagnosis of allergic rhinitis 

remit (if not an immune defect is possible). Serious 
underlying disease is unlikely in children who are grow- 
ing normally and who do not have problems beyond the 
upper respiratory tract. 

In adults an extensive drug history may reveal overuse 
of topical alpha agonists or the possibility of aspirin or 


Allergic rhinitis 

Infectious rhinitis 

non-infectious rhinitis 



Intermittent / persistent 
Mild / moderate / severe 


Non-viral non-bacterial (Protozoa / fungi) 
Drug-induced (P blokkers / vasodilators / 
contraceptives / aspirin / NSAID) 
Hormonal (hypothyroidism / pregnancy) 
NARES (some have local IgE production) 
Occupational (LMW agents / irritants) 
Atrophic / rhinitis of the elderly 

Acute / chronic 

Mild / moderate / severe 

Figure 2 Differential diagnosis of rhinitis/rhinosinusitis. 

NSAID hypersensitivity that usually starts in adult life. 
The latter cannot be discounted if no such drug has 
been safely taken in recent months and a challenge may 
be necessary. 

Hormonal rhinitis can occur, so questions about hor- 
mone therapy, possible thyroid auto-immunity, or preg- 
nancy are needed. 

Atrophic rhinitis can be a primary condition attributed 
to Klebsiella ozaenae or secondary to excessive surgery 
or radiation. 

Neurogenic rhinitis is incompletely understood but is 
usually non-inflammatory, commoner in females and 
less likely to be associated with asthma. It may com- 
mence at a time of great stress. Old man's drip is 
thought to be hormonal since it responded to testoster- 
one before therapy with ipratropium bromide was found 
to be effective. 
3 Rhinosinusitis 

Rhinitis frequently co- exists with sinusitis, so the cor- 
rect term in patients with symptomatic inflammation of 
the sinus cavities is rhinosinusitis. 

Rhinosinusitis including nasal polyps (NP) is defined 
as inflammation of the nose and the paranasal sinuses 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 4 of 39 

characterized by two or more symptoms, one of which 
should be either nasal blockage/obstruction/congestion 
or nasal discharge (anterior/posterior nasal drip), +/- 
facial pain/pressure, +/- reduction or loss of smell; and 
either endoscopic signs of polyps and/or mucopurulent 
discharge primarily from middle meatus and/or; 
oedema/mucosal obstruction primarily in middle mea- 
tus, and/or Computerised Tomography (CT) changes 
showing mucosal changes within the ostiomeatal com- 
plex and/or sinuses. 

The EP 3 OS document proposes to define the disease 
according to the duration of symptoms: 

Common cold/acute viral rhinosinusitis is defined as 
an acute rhinosinusitis lasting <10 days. 

Acute (non-viral or bacterial) rhinosinusitis is defined 
by an increase in symptoms after 5 days or PER symp- 
toms after 10 days with <12 weeks duration. 

Chronic rhinosinusitis/NP is defined symptoms for 
>12 weeks. 

The disease can be divided into MILD, MODERATE 
or SEVERE based on the total severity VAS score (0-10 
cm): MILD = VAS 0-3; MODERATE = VAS 3.1-7; 
SEVERE = VAS 7.1-10. 

As is the case with AR, patients with rhinosinusitis 
should be asked for the following: 

♦ onset of symptoms (since birth, adolescence or 

♦ timing of symptoms (acute vs chronic disease) 

♦ severity of symptoms (mild, moderate or severe) 

♦ provoking factors e.g. microbial or occupational 

♦ alleviating factors e.g. holiday away from home/ 

♦ seasonal aggravation in allergic patients 

♦ effects of treatments tried in the past 

♦ intolerance to medication e.g. aspirin 

♦ associated bronchial symptoms 

♦ familial history of sinus disease (NP disease) 


Adequate time and attention should be given to take a 
complete and accurate history both of rhinitis symptoms 
and those of possible co- morbidities. The history 
should suggest further diagnostic tests needed for a 
proper diagnosis. All rhinitis patients should have speci- 
fic IgE tests unless the history itself is diagnostic e.g. 
recurrent symptoms confined to a known pollen season 
with remission by avoidance. 

A subgroup of patients with rhinitis symptoms need to 
be referred to an ENT specialist for nasal endoscopy. 
ENT referral is needed for: 

- unilateral nasal problems 

- nasal perforations, ulceration or collapse 

- sero-sanguineous discharge 

- severe crusting within the nasal cavity 

- recurrent infection 

- periorbital cellulitis (refer urgently) 

- severe sleep problems 

Quality of Life Instruments in Rhinology 


The importance of quality of life issues in nasal disease 
has been well recognized. The effects of disease on daily 
functioning, work, leisure and school as perceived by 
the patient are considered as an important characteristic 
of rhinitis severity 1 . Moreover, assessment of quality of 
life is one of the standard outcome measures in clinical 
trials acknowledging the fact that the classical outcome 
variables may only partially characterize the disease of 
the patient. 


Health related quality of life has been defined as "the 
functional effects of an illness and its consequent ther- 
apy upon a patient, as perceived by the patient [6]. 
Quality of life instruments aim to describe these effects. 
The patient's perspective is particularly important. 

Generic and disease-specific questionnaires 

In general, two types of instruments are available, gen- 
eric and disease-specific questionnaires. Generic ques- 
tionnaires measure physical, psychological and social 
domains in all health conditions irrespective of the 
underlying disease. Those questionnaires allow the com- 
parison between healthy and diseased subjects. Disease- 
specific instruments have been designed by asking 
patients what kind of problems they experience from 
their disease. Both the frequency and the importance of 
impairments are measured by means of the question- 
naires. These instruments have the advantage that they 
describe the disease-associated problems of the patients. 

There are important differences in the use of these 
instruments. Specific questionnaires have better discri- 
minative and evaluative properties. On the other hand 
specific and generic instruments might cover different 
aspects of disease [7], Moreover, an important charac- 
teristic of generic instruments is the ability to measure 
across diseases, thereby allowing for comparisons 
between different disorders. Finally, some generic ques- 
tionnaires such as the Euroqol 5D [8] have been devel- 
oped for cost-effectiveness studies. 

Usage of instruments 
Clinical trials 

Both generic and disease specific can be used in clinical 
rhinitis and rhinosinusitis trials. The responsiveness to 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 5 of 39 

change seems to be better with disease specific instru- 
ments. Generic instruments are less effective with mild 
disease [9]. From the many generic instruments the 
Short Form-36 health survey (SF-36) [10] and SF-12 
[11] are commonly used in rhinitis and rhinosinusitis. In 
rhinosinusitis the McGill pain questionnaire [12] and 
the Glasgow benefit inventory (GBI) have been applied 
in several trials. The most frequently used rhinitis speci- 
fic instruments [13] are the RQLQ [14] and its varia- 
tions for adults (standardized RQLQ, mini-RQLQ [15]) 
and other age groups and Adolescent RQLQ [16]. A ser- 
ies of instruments has been developed to assess rhinosi- 
nusitis. From these questionnaires the Rhinosinusitis 
Disability Index (RSDI) [17] and in particular the Sino- 
Nasal Outcome Test 20 (SNOT-20) [18] are the most 
common outcome measures. 
Cost-effectiveness studies 

Cost-effectiveness studies use specific instruments 
designed for this kind of analysis. The Euroqol-5D [19] is 
a generic measure of health status that provides a simple 
descriptive profile and a single index value that can be 
used in the clinical and economic evaluation of health 
care. The (RSUI) was developed as a disease specific pre- 
ference-based measure of rhinitis symptoms, also to be 
used in cost-effectiveness studies [20]. To date, there are 
no cost-effectiveness trials in patients with rhinitis or 
rhinosinusitis using these instruments. This can be attrib- 
uted to a lack of cost-effectiveness studies in this area. 
Clinical practice 

Ideally, clinicians should be able to estimate the burden 
of disease in their patients. A quality of life question- 
naire might be helpful. Many HQLQ instruments how- 
ever are developed for use in clinical trials. In a recent 
systematic review 13 disease specific HQLQ tools for 
adults were evaluated [21]. One questionnaire, the Rhi- 
nasthma [22] evaluates patients with rhinitis and 

asthma. Several questionnaires can be used in practice 
[23-31] (see table 1). 

Rhinitis control Quality of life will improve if the dis- 
ease is well controlled. HRQL questionnaires, however, 
do not estimate to what extent a disease is under con- 
trol. In recent years new tools for asthma control have 
been developed and validated. Rhinitis tools are being 
developed, but not published yet. 

Evidence based instruments 

The development of HQLQ instruments comprises a set 
of procedures for validation, determination of reliability 
and responsiveness. In general, these tools are better 
studied than classical outcome measures. However, in a 
recent systematic review of the quality of disease specific 
HQLQ four instruments only were identified as ade- 
quate in terms of discriminant validity (important for 
cross-sectional analysis) and responsiveness (important 
for longitudinal studies). For rhinitis the RQLQ and 
standardized RQLQ and for rhinosinusitis the RSOM-31 
and the RhinoQOL appeared to be effective [18]. 


The choice for an instrument depends on its purpose 
and the target population. For purposes of research 
other questionnaires are needed than for the evaluation 
of patients in clinical practice. The above-mentioned 
review gives some guidance to clinicians interested in 
the evaluation of quality of life in patients affected 
with AR and RS [21]. It has been suggested that the 
use of both generic and specific instruments may be 
useful [7], although this may not be always the case. 
As the outcome of quality of life assessment is only 
partly associated with clinical outcome measures, it is 
recommended to evaluate patients with both HRQL 
and medical measures. 

Table 1 Instruments used in allergic rhinitis and in chronic rhinosinusitis 


Disease specific 



Pediatric RQLQ, adolescent RQLQ 


SF-36, SF-12, 15D [23], EuroQol 5D 

RQLQ, standardized RQLQ, mini-RQLQ, Nocturnal Quality of Life 
Questionnaire (NQLQ) [24], Rhinitis Outcome Questionnaire [25] #, Rhinitis 
Symptom Utility Index (RSUI) 



(CHQ) [26] 

SN-5 quality of life survey [27] 


SF-36, SF-12, McGill pain questionnaire (MPQ), 
EuroQol 5D, Glasgow benefit inventory (GBI) 

Rhinosinusitis Outcome Measurement (RSOM-31) [18] #, Rhinosinusitis 
Disability index (RSDI) #, sinonasal outcome test 16 (SNOT-16) [28] #, SNOT- 
20#, Chronic sinusitis survey (CSS) [29], RhinoQol [30], Sinusitis outcomes 
questionnaire (SOQ) [31] 

# for use in clinical practice 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 6 of 39 

Nasal Examination 


In the evaluation of a patient with (sino-)nasal symptoms, 
it is indispensable to start with a good inspection of the 
nose and face, both during inspiration as well as during 
expiration. Major anomalies can be visualized directly, like 
nasal vestibulum stenosis in cleft lip patients (Figure 3), 
collapse of the nostrils during inspiration (Figure 4) or 
severe septal deviations. Therefore, the aim of inspection 
of the nose is to delineate any anatomical problems that 
can interfere with the nasal function both in rest as well as 
during inspiration. 

Inspection is the visual investigation of the external 
structures of the nose and beyond, in order to get a first 
and superficial impression of the nose and nasal 

During history taking and clinical examination, it is 
important to look at the nasal anatomy, both at rest as 
well as during inspiration. With the aid of a light source, 
one can even better evaluate the bony, cartilaginous and 
skin parts that constitute the nasal dorsum. 
The following nasal aspects are evaluated: 

- The shape: congenital or acquired abnormalities of 
the ossa nasalia, middle vault and external valve area. A 
widened dorsum of the nose can indicate the presence of 
nasal polyps, caused by the dispersing of the ossa nasalia 
by nasal polyps (Woakes Syndrome, typical for CF). A 
horizontal nasal crease across the dorsum of the nose 
supports a diagnosis of AR. The presence of vestibular 
stenosis (Figure 3), alar collapse at the time of inspiration 
(Figure 4) and/or narrow middle vault are associated 
with nasal obstruction and can be observed during exter- 
nal inspection of the nose during inspiration. 

- The position: examination of the bony nose bridge, 
mostly deviated by trauma, can be hampered by the 
post-traumatic swelling. Examination of the cartilagi- 
nous tip of the nose, mostly deviated during growth. 

Figure 3 Inspection of the nose showing distortion of the 
anatomy at the level of the nasal entry (in cleft lip patients) 

Figure 4 Inspection of the nose showing alar collapse during 

- The covering skin of the nose: search for color 
changes, edema, skin lesions, fistulas or scarification. 

- The surrounding structures: forehead, eyes, cheeks 
and upper lip. 

II. Palpation 

This simple and inexpensive act is a proper manner to 
trace pathology of the skin, the tissues, the bony and 
cartilaginous parts of the nose. 

To evaluate the nose with the fingertips, in order to 
search for shape or tissue anomalies, painful or sensitive 
areas, and/or lack of tip support mechanisms. 

Examination of the skin, underlying tissues, the bony 
and cartilaginous parts for irregularities, abnormal mobi- 
lity, pressure pain and tip support. 

A proper light source is necessary for an accurate 
inspection. With palpation one can detect a nasal valve 
dysfunction, particularly with the Cottle test. The 
cheek of the evaluated side is gently pulled laterally 
with one or two fingers, which opens the valve. The 
examiner then asks the patient to breathe and then 
evaluates if breathing is subjectively better after pulling 
the cheek. A positive test result is when the patient 
feels less resistance with the valve opened. This test is 
easy and quick to perform, but has a high false positive 
result rate. 

In case of lack of tip support, the tip elevation test 
(Figure 5) may provide the examiner with valuable infor- 
mation on the cause of nasal obstruction. The patient is 
asked for improvement of nasal breathing by holding 
the nasal tip in a position with a straight naso-labial 
angle as depicted in Figure 5. 

Anterior Rhinoscopy 


Anterior rhinoscopy makes a quick but limited internal 
inspection possible of the anterior parts of the cavum 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 7 of 39 

Figure 5 Tip elevation test for evaluation of improved 
breathing by restoration of normal tip support 


An inspection of the clinical status of the anterior parts 
of the nose. Trace nasal discharge or mucosal aberra- 
tions like swelling, crusting, mucosal perforations, large 


Internal inspection of the vestibulum and cavum nasi 
with the aid of an examination lamp fixed to a head- 
band and a nose speculum (Figure 6). 


With a forehead light and nose or ear speculum. Without 
speculum, the tip of the nose can simply be pushed 
upwards and so, one can get a first impression of the posi- 
tion of the septum and of the head of the first concha 
(practical in case of examination of an infant). A right- 
handed observer takes the speculum in the right hand, 
while the left hand is used to position the head of the 
patient. The speculum, inserted under an angle of 45°, 
spreads the alar cartilages and pushes aside the hairs in 

Figure 6 Anterior rhinoscopy allowing the evaluation of 
mucosal and/or anatomic pathology at the anterior part of the 
nasal cavity 

the nose. The nasal septum must not be touched, because 
it is very sensitive. When the head of the patient is bend 
forward, the anterior part of the inferior meatus and con- 
cha can be visualized, by bending the head of the patient 
backwards, the anterior part of the middle meatus and 
concha. At last the speculum has to be removed closed to 
avoid avulsion of the hairs in the nose, which is very pain- 
ful. It must not be forgotten to get a look in the oral cavity 
and pharynx for signs of pharyngitis, post nasal drip can 
cause lymphoid hyperplasia, resembling cobble stones. 

Nasal inspection can be supplemented by the so-called 
mirror test (Figure 7). By holding a cold mirror or small 
metal plate under the nostrils, the airflow during nasal 
expiration can be assessed. A lack of fogging indicates 
an inadequate nasal flow, or major asymmetrical fogging 
indicates unilateral obstruction. 


Anterior rhinoscopy is limited in its evaluation of the 
entire nasal cavity. Therefore, complete and thorough 
examination using nasal endoscopy is advocated for 
patients with nasal symptoms. For example, small polyps 
may not be seen by anterior rhinoscopy. 


Possible clinical findings during anterior rhinoscopy are 
rhinorrhoe with transparent or discoloured secretions, 
asymmetries (mostly of the nasal septum), mucosal 
aberrations or edema, nasal polyps, neoplasms, corpora 
aliena, etc. One can assess the accessibility of the nose 
and the shape of the conchae. 

Posterior Rhinoscopy 


This examination is performed to inspect the posterior 
parts of the cavum nasi, the choanae, the posterior parts 
of the lower and middle concha nasalis, the posterior 

Figure 7 Mirror test for evaluation of the condensate of 
expired air on a cold metal instrument or mirror 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 8 of 39 

septum, the nasopharynx with the adenoid and the ostia 
of the auditory tube. 


An inspection of the posterior parts of the cavum nasi and 
the nasopharynx with the aid of a small throat mirror. 


Posterior rhinoscopy is performed with a forehead light, a 
tongue spatula in the left hand and a small throat mirror 
in the right hand. Cooperation of the patient and skills of 
the observer are required. Firstly, the mirror has to be 
heated till body temperature, otherwise it will be dimmed. 
Then the tongue spatula is placed in the middle of the 
tongue base whereby the tongue will be pushed down 
gently. The mirror can be advanced towards the space 
beyond the uvula. The act has to be performed carefully 
because touching the pharyngeal mucosa will trigger a 
vomiting reflex. When the palatum molle is too stringent, 
ask the patient to breathe calmly by the nose whereby the 
palatum molle relaxes and so the view extends. 


Possible conditions are congenital choanal atresia, 
acute adenoiditis, irritation of the rhinopharynx, post- 
nasal discharge, antro-choanal polyps, and Thornwald 


At present, this examination is not routinely being per- 
formed, and is often replaced by nasal endoscopy. 

Nasal Endoscopy (rigid and flexible) 


In comparison with the anterior and posterior rhino- 
scopy, nasal endoscopy offers the advantage of global 
evaluation of the endonasal cavity (Figure 8). 


Due to endoscopy, a good evaluation of the septum, the 
whole nasal cavity and the nasopharynx is possible, but 
also the area of the middle meatus which has clinical 
importance in rhinosinusitis. 


Nasal endoscopy allows inspection of the internal cavum 
nasi, with a bigger range of view and details in compari- 
son with anterior and posterior rhinoscopy. 


Nasal endoscopy is performed by a flexible or rigid 
scope which is attached to a strong light source by glass 
fibre. For diagnostical examination, a scope with an 
optic angle from 25-30° is used with a calibre of 2,5-4 
mm (Figure 8). Other optics are mostly used in surgery. 
Nasal endoscopy can eventually be preceded by local 
administration of anaesthetic drugs preferably in combi- 
nation with a decongestivum. At first, the bottom of the 
nose unto the nasopharynx is to be inspected with an 
evaluation of the septum nasi, the lower turbinate, the 
choanae and the nasopharyx. Afterwards, the scope fol- 
lows the edge of the middle concha towards the rostrum 
sphenoidale, with information about the middle and 
upper concha, the drainage from the sinuses, possible 
accessory ostia from the maxillary sinus and the aper- 
ture of the sphenoid sinus. At last, there must be 
attempted to get a view of the osteomeatal complex, the 
ethmoidal bulla and the access to the frontal sinus. 


Allergic and inflamed mucosa, secretions or swelling in 
the middle meatus, and possible presence of nasal 
polyps should be evaluated. Although the usefulness of 
nasal endoscopy in the evaluation of the nasal conges- 
tion is obvious, no clinical trials were found to support 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 9 of 39 

this statement. It was shown to be moderately sensitive 
and highly specific in predicting CT scanning results in 
patients with CRS [32] . Nasal polyps can be viewed with 
endoscopy, their presence and severity can be scored by 
validated systems with a good reproducibility. However, 
a correlation between size of polyps and the subjective 
symptom of congestion cannot be found. This discre- 
pancy between objective findings and subjective com- 
plaints make endoscopy less suitable for assessment of 
severity. Still, when nasal polyps are present, nasal endo- 
scopy scoring is very useful in treatment evaluation [33]. 
A possible semi-quantitative score for nasal polyps can 
be obtained at baseline and at regular intervals following 
therapeutic interventions (Table 2). 

Diaphanoscopy of the frontal and maxillary sinus 


Transillumination of human tissue or a cavity, like a 
sinus, with a light source to evaluate the opacity of the 
hollow sinus. 


Transillumination of the maxillary sinus is performed 
with a light source in the mouth of the patient, 
watched in a darkened room. If the sinus is accessible 
(vacant), the light shines through the sinus and 
through the pupil. The frontal sinus can be investi- 
gated by diaphanoscopy if the light source is placed at 
the bottom of the frontal sinus. This examination is 
only useful in case of a unilateral acute maxillary or 

Table 2 Endoscopic appearance scores 

Characteristic Baseline and Follow-up 

Polyp left (0,1,2,3) 
Polyp right (0,1,2,3) 
Oedema left (0,1,2) 
Oedema right (0,1,2) 
Discharge left (0,1,2) 
Discharge right (0,1,2) 

Postoperative scores to be used for outcome assessment only 

Scarring left (0,1,2) 

Scarring right (0,1,2) 

Crusting left (0,1,2) 

Crusting right (0,1,2) 


Polyps: 0 Absence of polyps 

1 Polyps in the middle meatus only 

2 Polyps beyond the middle meatus but not blocking the nose completely 

3 Polyps completely obstructing the nose 
Oedema: 0 Absent; 1 Mild; 2 Severe 

Discharge: 0 No discharge; 1 Clear, thin discharge; 2 Thick purulent discharge 
Scarring: 0 Absent; 1 Mild; 2 severe 
Crusting: 0 Absent; 1 Mild; 2 severe 

frontal sinusitis of an adult patient, who did not yet 
undergo sinus surgery. 

Although the shortcomings of diaphanoscopy soon 
became apparent, the method was widely used for about 
half a century, but in the end could not compete with 
modern techniques of radiography and ultrasound [34]. 


Inspection, palpation and anterior rhinoscopy are easy 
and rapid ways to examine a nasal problem without 
inconvenience to the patient. Therefore they should be 
the corner stone of every physical examination. Anterior 
rhinoscopy allows a limited internal inspection of the 
nasal cavity. In the majority of patients with persistent 
nasal symptoms, a complete and thorough examination 
of the nasal cavity is warranted using nasal endoscopy. 
For example, small polyps may not be seen by anterior 
rhinoscopy. Nasal endoscopy has been particularly use- 
ful in assessing the nasal airways in the region just 
below the olfactory cleft. Rigid endoscopy has proven to 
be more patient friendly and supplies a better image 
than flexible endoscopy. Patients awarded each type of 
scope a pain score on an analogue scale, according to 
the level of discomfort experienced, and the operator 
noted the number of structures seen. Significantly more 
structures were visualized with the rigid scope than the 
flexible scope. The pain scores were similarly in favor of 
the rigid scope, showing a trend to less discomfort [35]. 

Allergy Tests Including Provocation 

Rationale and objectives of diagnostic tests in allergy 

In the diagnostic process of allergic rhinitis we assume 
that allergen-specific IgE is the triggering factor of 
symptoms and of the underlying inflammatory process. 
Thus, the main goal of the diagnostic tests is to demon- 
strate both the presence and functional relevance of 
such IgE. In fact, the presence of specific IgE alone (sen- 
sitization) does not necessarily imply the existence of 
allergic symptoms, and there are a relevant number of 
individuals who are sensitized but who are not clinically 
allergic [36]. 

In patients with symptoms suggestive of AR, further 
diagnostic testing is required for optimal diagnosis and 
management (Figure 9). The presence of specific IgE can 
be demonstrated either in vivo (skin tests, SPT) or in 
vitro by detecting allergen-specific IgE in the blood 
(RAST, CAP-RAST and equivalent assays). Currently, 
SPT are unanimously considered the gold standard and 
the first-line approach for the detection of allergic sensi- 
tization, due to its' efficiency, safety and relatively low 
costs. The biological assays (CAP-RAST) have an equiva- 
lent efficiency, but due to costs are considered a second 
choice to be used only in special situations. The basophil 
degranulation tests require a special laboratory apparatus 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 10 of 39 




Negative/not feasible 
discordant from 
clinical hsitory 

Positive and in 
agreement with 
clinical hsitory 



Negative/not feasible 
discordant from 
clinical hsitory 

(search for nasal IgE?) 



Figure 9 Diagnostic algorithm for the diagnosis of AR. 

and, therefore, do not represent a routine option in the 
diagnostic workup. In addition, the functional role of spe- 
cific IgE can be demonstrated in vitro by basophil activa- 
tion tests or in vivo by the allergen-specific provocation. 

The nasal provocation tests aim at eliciting a nasal 
response, by delivering appropriate allergens to the 
nose. There is a wide variability of substances, measure- 
ments and evaluation techniques for nasal challenges 
(Figure 10). The purpose of the allergen specific provo- 
cation, is to reproduce at some extent the reaction 
occurring during the natural exposure to allergens. 
Thus, nasal allergen challenges allow demonstrating 
both the presence of allergen-specific IgE and the causal 
role of the allergen. The same happens with occupa- 
tional substances or with aspirin, although in these cases 
the mechanism maybe non IgE-mediated. The non aller- 
gen- specific challenges evoke a non-specific 





Hyperosmolar solution 




Paper disks 
Challenge chamber 


Symptom score 
Inspection of mucosa 
Weight of secretions 
Number of sneezes 

Nasal flow/patency ► 

Acoustic rhinometry 
Peak flow 


Brushing, scraping 



Figure 10 Practical approaches for nasal provocation test. 

inflammatory response, and demonstrate the existence 
of a nasal hyperreactivity. 

Skin prick test (SPT) 

The SPT technique is currently considered the gold stan- 
dard method for the diagnosis of allergic rhinitis. With a 
trained investigator, they are highly reproducible [37,38]. 
Prick tests should be performed according to a rigorous 
methodology, with standardized diagnostic extracts, and 
always must include a negative (saline or diluent) and a 
positive control (histamine HQ 0.1%). Skin tests should 
be read at the peak of reaction (approximately at 15 min- 
utes) by measuring the extension of wheals (Figure 11). 
The diagnostic and clinical significance of late reactions 
is not known. The scoring of the positivity is given 
according to EAACI recommendations, and the interpre- 
tation of a positive test must be integrated with the clini- 
cal history, since a positive SPT does not always imply a 
clinically relevant sensitization. 

False positive reactions may occur, if a dermographism 
is present, but this can be ruled out with the use of the 
negative control. 

False negative may occur due to: 

a) weak potency of the extract; 

b) inadequate technique (weak puncture); 

Figure 11 Skin prick test with evaluation of wheal and flare 
reaction on the skin at the site of allergen deposition 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 11 of 39 

c) interfering drugs. Systemic antihistamines are the 
most important drugs that reduce the skin reaction 
(Table 3). Thus, antihistamines must be discontinued at 
least 5 days before the SPT (for review see 11). On the 
other hand, antileukotrienes do not interfere with SPT 
and can be continued [39]. 

Intradermal tests are not of choice for the diagnosis of 
respiratory allergy, since they do not perform better than 
SPT and can induce false positive results. On the other 
hand, intradermal tests remain an essential part of the 
diagnostic workup for hymenoptera allergy [40]. The 
scratch test is no longer in use. 

Atopy patch tests involve epicutaneous patch tests 
with allergens known to elicit IgE-mediated reactions. 
Commercial reagents are available for a few allergens, 
and have been standardized regarding the use of vehicle 
and dose-response relationships. A subset of patients 
with atopic dermatitis show only atopy patch test posi- 
tivity while specific IgE to the same allergen remains 
negative [41], but the atopy patch test is usually not 
relevant for the diagnosis of respiratory allergies. 

Detection of allergen-specific IgE 

The first method used for the measurement of serum 
allergen specific IgE has been the radioallergo sorbent test 
[42]. This has been now replaced by immune-enzymatic 
methods, including the widely used CAP assay. With these 
assays the level of specific IgE is expressed as kU/L, 
according to calibration curves, and the cut-off IgE level 
above which the test is positive is usually 0.35 KU/1. How- 
ever, some sensitized subjects have an IgE level below this 
cut-off. The measurement of serum-specific IgE is usually 
less sensitive than skin prick tests [43] and the worst cor- 
relations between SPT and IgE assays are obtained with 
mold, food extracts and non standardized extracts. In gen- 
eral, the correlation between a strongly positive response 
to a skin test and the detection of serum-specific IgE and 
between a negative response to a prick test and the lack of 
detection of serum-specific IgE is very good. As in skin 
tests, the presence or absence of specific IgE in the serum 
does not imply a clinically relevant allergy. As mentioned 
above, for inhalant allergens, skin test responses represent 

the first-line diagnostic methods and when they correlate 
with the clinical history, in vitro tests are not necessary [1]. 

It has been suggested in the past that some patients 
may have a local IgE immune response without systemic 
IgE [44]. It has been recently shown that in a subset of 
patients the presence of specific IgE in the nasal mucosa 
can be demonstrated [45]. Nonetheless, the measure- 
ment of IgE in nasal secretions cannot be routinely 

The presence of functionally relevant specific IgE can 
be demonstrated by putting the allergen into contact 
with basophils and subsequently detecting their activa- 
tion by cytofluorometry. This basophil degranulation 
test has been proposed for specific conditions, such as 
drug allergies, but is not recommended at all for the 
diagnosis of respiratory allergies, and it is used only for 
research purposes. 

Serum-total IgE is measured using either radioimmu- 
noassay or enzyme assay. In normal subjects, levels of 
IgE increase from birth to adolescence and then 
decrease to reach a plateau after the age of 20-30 years. 
In adults, levels of over 100-150 KU/1 are considered to 
be above normal. Nevertheless, an increase of total IgE 
correlates weakly with the presence of allergic diseases. 
Total IgE maybe increased in other conditions such as 
smoke and parasitic diseases. Thus, the measurement of 
total-serum IgE should no longer be used for screening 
or allergy diagnosis [1]. 

Allergen specific nasal challenge (ASNC) 

The ASNC procedure, also known as specific nasal pro- 
vocation test (SNPT) or nasal allergen challenge (ANC) 
involves the delivery of a small quantity of the allergen 
into one (or both) nostril, in order to elicit the allergic 
reactions, if allergen-specific IgE is present in the nasal 
mucosa. By using progressively increasing amounts (or 
concentrations) of the allergen, a threshold dose can be 
also established. Recently, the availability of recombinant 
purified allergens has suggested the possibility to per- 
form challenges with each specific allergenic protein, 
but the role of such approach in clinical practice is still 
not defined. 

Table 3 Drugs affecting the results of skin tests 


Duration of Suppression (days) 

Cetirizine, desloratadine, ebastine, levocetirizine, mizolastine 



Chlorphenamine, promethazine 









Inhaled steroids 

Systemic steroids 




Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 12 of 39 

The procedure of allergen provocation was proposed 
more than one century ago and began to be systemati- 
cally investigated starting from the 1950ties. Nowadays, 
there are some official documents available, where an 
attempt to standardize the procedure has been made 
[46]. The main advantages of ASNC are the simplicity 
of execution, the low cost and the safety. On the other 
hand, the procedure is still poorly standardized and the 
technical details (amount of allergen, interval between 
doses, dilutions, positivity criteria) are largely variable 
among centres. The main indications of ASNC are 

a) to demonstrate the causal role of an allergen, 

b) to identify the clinically relevant allergen(s) in poly- 
sensitized subjects, 

c) to evaluate the effects of a treatment 

d) to study the inflammatory phenomena (Table 4) 

e) to evaluate the role of occupational allergens. 
When an allergen is introduced into the nose, the IgE- 

mediate reaction immediately takes place and the classic 
symptoms appear within seconds. Symptoms slowly sub- 
side within 4-6 hours, may re-appear after several hours 
in case of a late phase reaction. The biphasic reaction 
can be easily demonstrated by nasal scrapings to assess 
the presence of the inflammation. 

The SNPT can be evaluated in many different ways. 
The most common and practical is the measurement of 
the four classic nasal symptoms by an ordinal scale (0 = 
absent to 3 = severe), being the test positive if a cumula- 
tive score of 5 or more is obtained. Alternatively, a 
visual analog scale can be used. Another semi-quantita- 
tive evaluation is the weight of nasal secretions, but this 
is less practical and is used only in research settings. 

A quantitative assessment of the ASNC can be made 
by instrumentally measuring the nasal flow or resistance, 
by nasal peak flow meter, acoustic rhinometry or rhino- 
manometry. These investigations will be dealt with 
further in the document. 

Other possible modalities to evaluate the effect of 
allergen challenge are the assessment of the inflamma- 
tory infiltrate by nasal scraping/brushing (with differen- 
tial cell count), or the measurement of specific 
mediators in nasal lavage, including tryptase, alpha2 
microglobulin, albumin, leukotriens, interleukins, eosi- 
nophil cationic protein and others (36-40). 

Aspirin nasal challenge 

The nasal challenge with aspirin is not truly an allergen 
challenge, since an IgE mediated mechanism is not 
involved. Nevertheless it has the value of a specific chal- 
lenge and it is used to diagnose aspirin intolerance in 
the context of the aspirin hypersensitivity with respira- 
tory manifestations. The nasal challenge with aspirin 
was introduced later than the oral and bronchial chal- 
lenge [47], but has gained popularity since it rarely 
induces systemic reactions. Nasal aspirin challenge is 
used in patients with severe asthma in whom oral or 
bronchial aspirin challenges are contraindicated. 

The aspirin challenge is sufficiently standardized and 
reproducible [48], although the possibility of false nega- 
tive results exists and the negative predictive value is 
lower than the oral and bronchial challenges. For this 
reason, it is agreed that where an aspirin intolerance is 
suspected and the nasal challenge is negative, the oral 
challenge must be performed. The nasal aspirin challenge 

Table 4 Practical aspects of ASNC 


Acute bacterial or viral rhinosinusitis. 
Acute exacerbation of allergic disease. 
History of previous anaphylactic reaction 
Severe general diseases 

Recent ENT surgery (6-8 wks) 


Weak extract 

nasal antihistamine (1 day withdrawal) 
oral antihistamine (3 day withdrawal) 
nasal steroid (7 day withdrawal) 


Let the patient be adapted to room temperature 
Inspect nasal cavity 

Spray or apply saline as negative control 
Perform measurement(s) 
Instruct to avoid nasal breathing 

Apply the allergen into one nostril and re-evaluate after 10-15 minutes 

Proceed on with increasing concentration in the other nostril 

Use both active and plasebo tests for diagnosis for occupational rhinitis 


Demonstration of the causal role of an allergen 
Identification of the most relevant allergen(s) 
Evaluation of the effect of a treatment 
nvestigating the inflammatory phenomena (research) 
Occupational rhinitis 

Nasal cycle 

Recent exposure to irritants 


Priming effect 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 13 of 39 

must be performed under medical supervision. Oral, 
nasal steroids and antileukotrienes should be discontin- 
ued at least 7 days before, whereas the withdrawal period 
is 3 days for antihistamines and 24 hours for deconge- 
stants and cromones. Lysine-aspirin solutions at 0.1, 1 
and 2 M are used at 10-minute interval steps. The eva- 
luation of the result can be either clinical (symptoms) or 
instrumental (acoustic rhinometry, anterior rhinomano- 
metry), and pulmonary function must be monitored dur- 
ing the challenge. 

Non-specific nasal challenges 

Nasal hyperreactivity is the capacity of the nasal mucosa 
to respond with clinical symptoms and inflammation to 
unspecific stimuli, which are not causing any mucosal 
reaction in normal subjects. Nonspecific nasal reactivity 
is common in patients with allergic rhinitis [49]. A wide 
variety of stimuli can be used to evoke nasal hyperreac- 
tivity. These stimuli may directly act on a single recep- 
tor such as histamine, adenosine monophosphate, and 
methacholine, or activate a more complex mechanism, 
such as mannitol, capsaicin, hyperosmolar solutions and 
cold air. 

The results obtained with non-specific nasal chal- 
lenges are often conflicting and difficult to interpret, 
due to the heterogeneity of methods, doses and out- 
comes. As an example, histamine and methacholine are 
both able to evoke a nasal reaction, that is more pro- 
nounced in subjects with rhinitis than in healthy con- 
trols [50], but only histamine is able to modify the nasal 
resistance. On the other hand, cold dry air was shown 
capable of differentiating between patients with peren- 
nial non-allergic rhinitis and healthy subjects, but hista- 
mine did not [51]. In addition, mannitol nasal challenge 
seems unable to activate mast cells, although a dose- 
response in eliciting symptoms has been reported for 
this test [52]. 

The adenosine monophosphate challenge is relative 
simple and reproducible and more sensitive than hista- 
mine challenge [53]. It has been proposed to predict the 
response to nasal steroids and as a surrogate marker to 
evaluate the anti-inflammatory effects of drugs. 

Nasal capsaicin challenge displays a dose-dependent 
response [54], and is able to detect the nasal hyperreac- 
tivity in seasonal allergic rhinitis. Due to its selectivity 
for sensory nerves, it is mainly used for experimental 
purpose to study the cough reflexes. 

The nasal provocation with cold dry air requires a 
special apparatus, and is currently used only for 
research purposes. Interestingly, the cold air provoca- 
tion has been reported to be able to discriminate 
between rhinitis alone and rhinitis associated with 
asthma [55], and between non-allergic rhinitis and 
healthy subjects [51]. 

A threshold dose discriminating healthy and diseased 
subjects has not been univocally established, as happens 
for instance in asthma. Another problem with those 
tests is that only few of them has been sufficiently stan- 
dardized. Finally, the role of nonspecific hyper-reactivity 
in distinguishing different forms of rhinitis has not been 
established yet. Thus, for the clinical purpose and diag- 
nosis of allergic rhinitis, the use of non-specific tests is 
not essential. 

Assessing the sense of Smell 


Several patients with rhinitis and/or rhinosinusitis com- 
plain of smell dysfunction, and treatment for these con- 
ditions aims at restoring olfaction. 


To objectively evaluate the capacity of an individual to 
smell environmental odours. 


Several techniques are currently available for the objec- 
tive evaluation of an individuals' smell capacity. The dif- 
ferent tests that have been reported in the literature are 
listed below and extensively described in the Appendix, 
with emphasis on their clinical use, validation and 
strengths and weaknesses. 

List of different diagnostic smell tests (Appendix 1) 

University of Pennsylvania Smell Identification Test 

Connecticut Chemosensory Clinical Research Center 
Test (CCCRC) 
Smell diskettes test 
Odourant confusion matrix 
Dutch odour identification test (GITU) 
YN-odour Identification Test (YN-OIT) 
T&T Olfactometer 

San Diego Odor Identification Test (SDOIT) 

Cross-Cultural Smell Identification Test (CC-SIT) 

Combined olfactory test (COT) 


Candy smell test (CST) 

Alcohol Sniff Test (AST) 

Culturally Adjusted University of Pennsylvania Smell 
Identification Test (CA-UPSIT) 
Kremer smell test 

Scandinavian Odour-Identification Test (SOIT) 

Pocket Smell Test [56] 

Eloit and Trotier Olfactory Test 

Ramdon Test 

Four-minute odour identification test 
Barcelona Smell Test (BAST-24) 
Nez du Vin smell test 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 14 of 39 


Smell testing should be an integral part of the diagnostic 
approach in patients with smell dysfunction, i.e. hypos- 
mia, parosmia or anosmia as presenting symptoms of 
sino-nasal disease, post-traumatic or post-viral smell dis- 
order. Smell dysfunction is a cardinal symptom of rhino- 
sinusitis with/without nasal polyps, but novel data 
suggest that also allergic rhinitis is often associated with 
a subjective reduction in smell capacity. 

Assessing the Sense of Taste 


To evaluate the capacity of taste of five basic taste sen- 
sations, i.e. salt, bitter, sour, umami and sweet, in 
patients complaining of dysfunction of smell and taste. 
Smell disorders may be associated with disturbed taste 
capacity, hence necessitating the evaluation of taste 
capacity in addition to smell capacity in these patients. 


Gustometry with application of taste substances and elec- 
trogustometry are the methods of taste examination. 
There are various ways of applying taste substances during 
gustometry examination. The stimuli used in gustometry 
are: citric acid or hydrochloric acid (sour taste), caffeine or 
quinine hydrochloride (bitter taste), sodium chloride (salty 
taste), saccharose (sweet taste), monosodium glutamate 
(umami taste). Electrogustometry, widely used by clini- 
cians to examine taste sensitivity, allows estimating the 
functioning of taste by means of electric excitability 
thresholds determined through the response to the irrita- 
tion of taste buds area with electrical current of different 
intensity. Electrogustometry is especially useful in estimat- 
ing the efficiency of sensory pathways. However, if we 
want to examine taste sensitivity to individual taste cate- 
gories we should use more laborious gustometry with the 
application of taste substances, which main advantage is 
the use of physiological stimuli [57]. Taste impairment 
may provide a good indicator to the course of some 
diseases such as diabetes mellitus in which hypogeusia 
predicts occurrence of degenerative complications. 
Dysgeusia may induce nutritional disorders and contribute 
to wasting in chronic liver disease, cancer, or human 
immunodeficiency virus infected patients. Mechanisms 
involved in dysgeusia are more than one in a patient. 
Taste disturbance may be secondary to a variety of causes 
that include zinc deficiency, lesions of the lingual epithe- 
lium, neurological impairment, and adverse events of 


Testing the taste capacity represents a diagnostic tool 
that is helpful in the clinical discrimination of smell and 
taste disorder in patients with smell problems 

complaining of combined loss of smell and taste, and in 
patients with isolated taste disorders. 

Nasal Nitric Oxide 


Nitric oxide (NO) is a colourless, odourless gas that is 
present in air exhaled through the mouth or nose. NO is 
produced from arginine and oxygen by nitric oxide 
synthase (NOS). Constitutively expressed neuronal and 
endothelial forms exist as well as an induced form, iNOS, 
which appears to be up regulated within the respiratory 
tract in response to pro-inflammatory signals. NO came 
to prominence for its role in vasodilatation [58] and sub- 
sequently as a neurotransmitter and inflammatory media- 
tor [59]. The role of NO in the airways is complex, 
possibly including antibacterial effects, pro-inflammatory 
effects, and regulation of blood flow and ciliary beat fre- 
quency. Exhaled NO (eNO) levels are raised in eosino- 
philic asthma [60] and measurement of this has become 
a standardised, but not yet widespread, tool in diagnosis 
and management of asthma. It can potentially provide a 
rapid, low cost, objective measure of lower airway 

Far greater levels of NO are produced in the upper 
than in the lower respiratory tract, with contributions 
from the sinuses and to a lesser extent from the nasal 
mucosa [61]. 


Measurement of nasal NO (nNO) may represent a use- 
ful tool for research purposes as well as for sreening for 
PCD. Nasal nitric oxide may be normal, raised or low- 
ered in disease states; however measurement may be a 
useful tool in the diagnosis and management of patients 
with chronic rhinosinusitis, nasal polyps, and CF, as well 
as in the diagnosis of PCD. Measuring both bronchial 
and nasal nitric oxide may assist the combined manage- 
ment of upper and lower airways. 

Nasal NO 

High levels of NO are produced constitutively in normal 
individuals within the paranasal sinuses by calcium-inde- 
pendent nitric oxide synthase, with levels measured at 
20-25 ppb [62]. Additionally, nitric oxide is also formed 
in the nasal mucosa by inducible NOS (iNOS) in 
response to inflammation. NO and its metabolites are 
toxic to micro-organisms and likely form part of the 
innate defense mechanism of the respiratory tract. NO 
may also stimulate cilia beat frequency within the epithe- 
lium and regulate nasal vascular tone. 


As for eNO, nNO can also be measured by chemillumi- 
nescence, using non-invasive techniques, providing 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 1 5 of 39 

immediate results. A number of different techniques have 
been used to ensure sampling from the upper airways only 
including breath holding and breathing against resistance. 
Guidelines for measurement have been published [63]. 

Sensitivity and specificity 

In contrast to measuring eNO, high baseline levels in 
nNO make background environmental NO levels less of 
a problem. Conversely, there is a high degree of inter- 
individual variability amongst healthy controls. More- 
over, there is also a significant degree of intra-individual 
variation over time, meaning that changes of 20-25% or 
less may be accounted for by normal variation rather 
than change in disease status or response to medication 
[64]. Additionally, the lack of universal standardization 
of testing procedures means levels recorded by different 
study groups vary considerably even amongst equivalent 
patient populations. The factors affecting eNO levels 
such as recent exercise or time of day, may similarly 
affect nNO measurements. Local factors such as nasal 
volume and patency may also be important. 


Despite the above limitations nNO has a number of 
potentially useful clinical applications. With regards to 
diagnosis, nNO is useful as a screening tool for patients 
with possible PCD; levels less than 100 ppb, particularly 
if these persist following decongestion, should stimulate 
investigation of mucociliary structure and function. The 
test is objective and may be easier to perform than a sac- 
charine clearance test in younger children. Similarly, 
nNO may provide a useful tool in diagnosis of CF in the 
context of upper respiratory tract symptoms; levels sig- 
nificantly lower than in controls have been reported in 
some studies, but not others. nNO has a potential role in 
the diagnosis and assessment of CRS, especially when 
associated with NP. Interestingly, despite the increased 
expression of iNOS in polyp epithelium [65], low nNO 
levels have been found in two large studies [66]. More- 
over, nNO inversely correlated with endoscopic NP size, 
CT scores and clinical severity of disease [67]. Conver- 
sely, in a study involving chronic rhinosinusitis patients 
with and without polyps, no correlation between nNO 
and CT scores was found, although patients were again 
found to have lower baseline nNO than controls [68]. 

Low nNO levels in chronic rhinosinusitis are thought 
to reflect obstruction at the sinus ostium and impairment 
of gas transfer out from the sinuses. This is supported by 
the finding of raised nNO following medical and surgical 
[65] treatment of rhinosinusitis with or without polyps. 

A number of recent studies have focused on the possi- 
ble use of humming to improve the sensitivity of nNO 
measurements. Weitzberg and Lundberg [69] found that 
humming induced a large increase in nNO and that these 

increases were not detected in patients with nasal polyps 
and sinus ostium obstruction. Furthermore, they suggest 
that absence of a normal response to humming during 
nNO measurement could be used to identify allergic rhi- 
nitis with sinus ostium obstruction. Whether this adds 
significant value to standard testing has yet to be fully 


Nasal NO is a useful measure to alert the clinician to a 
possible defect in mucociliary clearance (PCD, CF) and 
may have in the evaluation of the patency of the sinus 
ostium Variable baseline levels of nNO and the modest 
changes which may occur in allergic rhinitis or following 
treatment make nNO measurement of little value in the 
diagnosis and management of uncomplicated rhinitis. 

Nasal Sampling: lavages, cytology, biopsies 


Inflammation of the nose and sinuses is represented 
within the nasal mucosa and secretions. A variety of 
approaches have been used to monitor nasal inflamma- 
tion to investigate disease processes and to evaluate the 
effect of therapeutic intervention. These approaches 
include nasal lavage, different ways to obtain nasal cytol- 
ogy, nasal biopsy, and nasal NO-measurements. 


To compare different sampling methods of the nose and 
indicate the strength and weaknesses. 


Nasal blown secretions 

In this method, secretions in the nasal airways are 
blown onto wax paper or a plastic wrap and then placed 
onto a glass slide. Microscopic evaluation allows the dis- 
crimination of epithelial cells from granulocytes. 
Nasal lavage 

Nasal lavage is the introduction of fluid into the nasal cav- 
ity and its recovery after a predetermined dwell time. 
Nasal lavage is simple and rapid to perform, is well toler- 
ated, and provides a sample that allows us to evaluate the 
content of the secretion in the nasal lumen such as pro- 
tein, cells, mediators and cytokines. A range of techniques 
has been used to instil and recover fluid from the nasal 
cavity. Usually a volume of 2.5 mL to 5.0 mL 0.9% NaCl, 
prewarmed to 37°C, is instilled within each nostril with an 
80% recovery (range, 65% to 90%). An agent to disrupt the 
disulphide bonds of the mucus polypeptide chains can be 
included. In situations of extreme nasal blockage, the 
obstruction of the nasal lumen will limit the amount of 
fluid that can be retained within the nasal cavity, and 
smaller lavage volumes need to be used under such cir- 
cumstances. The consistency of the findings in allergic 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 16 of 39 

and infective rhinitis for a range of different measures in 
nasal lavage fluid supports the concept that this method of 
nasal evaluation provides reliable information of relevance 
to disease activity although normalization of the variable 
recovery can be difficult. However, repeated nasal lavage is 
associated with a significant reduction in histamine con- 
centration. Also there is considerable variability between 
subjects in eosinophil luminal recruitment and activation. 
Sinus packs or filter paper 

Pre-weighed sinus packs are placed on the floor of the 
nasal cavity between the septum and inferior turbinate for 
5 min and then placed back in a Falcon tube [70]. In order 
to mobilize the nasal secretions out of the sinus pack, the 
sinus pack is washed with 3 ml of 0.9% NaCl solution. The 
sinus pack is then placed into the shaft of a syringe and 
the sinus pack is squeezed by moving the piston of the syr- 
inge. After this first pressure the shaft containing the sinus 
pack is placed into a Falcon tube and centrifuged at 1,500 
g for 10 min to recover all fluid. 

If irritation of the nasal mucosa is an issue, thin filter 
paper that can be inserted without touching the nasal 
mucosa, can be used instead of sinus packs. The amount 
of secretion that can be absorbed in this way is however 
more limited [71,72]. 
Microsuction technique 

Nasal secretions can be collected by direct aspiration as 
has been described by Biewenga [73] . The samples can be 
collected by repeated aspiration into a pre-weighed plastic 
sampling tube immediately followed by aspiration of a 
known volume (1.0 ml) of PBS containing 10% of Mesna. 
Mesna acts by disrupting the disulphide bonds of the 
mucus polypeptide chains, and is necessary to obtain a 
good quality supernatant. The direct aspiration system 
combines the advantages of minimal irritation of the nasal 
mucosa with the facility to determine concentrations per 
gram of secretion. 
Nasal brush 

A small nylon brush used for cell sampling, is intro- 
duced in the middle meatus of the nose and turned 
carefully. The brush is immediately placed in a 5 ml 
polystyrene plastic tube containing 5 ml of PBS and is 
cut off just above the bristles. The brush can then be 
shaken vigorously in the solution and carefully brushed 
off against the wall of the tube. The tubes are centri- 
fuged at 400 g for 10 minutes [74]. Both the supernatant 
and cells can be used for analysis. Nasal brush give 
information on living epithelial cells which is an advan- 
tage over nasal lavage, however the sampled area is 
smaller. Brushing can reliably be used in babies and 
small children [75]. 
Nasal scraping 

Nasal scraping can be performed with the Rhinoprobe 
[76,77]. The cupped tip of the disposable probe is gently 
passed over the mucosal surface of the medial aspect of 

the inferior turbinate. Two or three short scrapes of the 
epithelial layer are made to obtain a sample. The speci- 
men is spread onto a plain slide and immediately fixed 
for at least 1 minute in 95% ethyl alcohol. Nasal scrap- 
ings give information on living epithelial cells sometimes 
in larger lumps which is an advantage over nasal lavage, 
however the area sampled is smaller than lavage and 

Nasal biopsy specimens 

Biopsy specimens can be taken from the nasal mucosa, 
usually from the inferior turbinate. High quality 2.5-mm 
biopsy specimens can be taken under direct vision with 
nasal biopsy forceps, such as Gerritsma forceps (Fok- 
kens' forceps), without visible damage to the epithelium 
of the sample and with sufficient depth of lamina pro- 
pria [78]. Local anaesthesia can be achieved by placing a 
cotton-wool carrier with 50 to 100 mg of cocaine and 3 
drops of epinephrine (1:1000) under the inferior turbi- 
nate without touching the area from which the biopsy 
specimen is taken. For light microscopic evaluation, the 
biopsy specimens are embedded in Tissue-Tek II OCT 
compound in a gelatin capsule and frozen immediately. 
Biopsies can be taken a number of times within one 
patient without causing significant problems [79]. The 
minimum number of sections required to give a suffi- 
cient number of fields to assure acceptable accuracy 
(5%) was determined to be 2 on the basis of a summa- 
tion average graph [80]. 

Comparison of different techniques 

A comparison of the different techniques is shown in 
Table 5. The choice of the technique depends on the 
diagnostic or research question asked. 

Data on the comparisons between different techniques 
are limited, but cells and mediators within nasal lavage 
have been reported to show some correlation [81]. 

Cells determined by nasal brush has been shown to be 
comparative to nasal lavage after nasal allergen provoca- 
tion [82]. Two studies show moderate to good correlation 
between cells recovered from biopsy and brush [83], 
however in one of these studies in which repetitive nasal 
provocations were given the number of inflammatory 
cells differed considerably on a day to day base [84]. 

Evaluation of Nasal Patency 


One of the primary functions of the nose is to humidify, 
filter and warm the inspired air. A patent nose with lack 
of anatomic and/or mucosal disease is a prerequisite for 
the transport of inspired air from the nose to the lower 
airways. A proper clinical examination of the nose 
allows the clinician to evaluate the nasal function. 
Inspection of the nose at rest and during inspiration 
may show normal anatomy or pathology causing 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 1 7 of 39 

Table 5 Comparison of different techniques 




Nasal blown secretions 

- easy to perform 

- subject must be able to blow nose 

- no information about mucosa 

Nasal lavage 

- easy to perform 

- luminal proteins, cells, mediators and cytokines 

- reliability depends ability of subject to close nasopharynx 

- dilution of mediators and cytokines 

- variable recovery of fluid 

- no information about mucosa 

Sinus packs or filter paper 

- no/limited dilution of mediators 

- may irritate the nose 

- cannot collect cells 

- no information about mucosa 

- more difficult than lavage 

Microsuction technique 

- no dilution of mediators 

- representative sample? 

- technically difficult 

- cannot collect cells 

- no information about mucosa 

Nasal brush 

- sample of epithelium 

- no sample of deeper layers 

- no information about nasal lumen 

- technically more difficult 

Nasal scraping 

- sample of epithelium 

- no sample of deeper layers 

- no information about nasal lumen 

- technically more difficult 

Nasal NO 

- non-invasive 

- measure of inflammation and blockage 

Nasal biopsy 

- sample of total nasal mucosa 

- no information about nasal lumen 

- technically difficult 

impaired nasal functioning like vestibular stenosis, col- 
lapse of the nostrils during inspiration called alar insuffi- 
ciency, asymmetry in the nostrils or severe nasal septal 
deviation. Anterior rhinoscopy enables the clinician to 
distinguish between mucosal and anatomic problems 
associated with nasal dysfunction. Other clinical tools 
like nasal endoscopy and posterior rhinoscopy allow 
experienced clinicians to evaluate the entire endonasal 
cavity and nasopharynx including the choanal region 

A more objective evaluation of nasal patency may be 
required in patients suffering from nasal obstruction 
due to anatomic or mucosal pathology, or in the context 
of provocation studies and clinical trials. Nasal patency 
can be assessed by different means, each technique deal- 
ing with a different aspect of patency: nasal flow, nasal 
cross-sectional diameter and nasal resistance during 
respiration. An overview is provided on the different 
techniques with technical aspects, advantages and disad- 
vantages of every technique and recommendations for 
use in practice. 


Nasal obstruction is often reported by patients with ana- 
tomic or mucosal nasal disease and can be scored sub- 
jectively on a visual analogue (VAS) scale. Objective 
evaluation tools of nasal obstruction are often warranted 
in patients suffering from nasal obstruction or for eva- 
luation of mucosal changes in provocation studies or 
clinical trials. 

Nasal patency can be monitored objectively by mea- 
suring the following parameters: 

1/nasal air flow passing through the nose during nasal 
respiration, evaluated with the nasal peak inspiratory 
and expiratory flow (PNIF and PNEF) 

2/the volume of the nasal cavity evaluated with acous- 
tic rhinometry and 

3/the nasal airflow and pressure during nasal respira- 
tion evaluated with rhinomanometry. 

Differences exist in indication for clinical use of each 
technique, the interpretation of the results, the valida- 
tion of the technique, and the cost of the equipment. 


1/Peak nasal inspiratory flow (PNIF) 

Nasal peak flow evaluation (Figure 12) represents a physio- 
logic measure of the air flow through both nasal cavities 
during forced inspiration and/or expiration expressed in 
liter per minute. The PNIF is the best validated technique 
for the evaluation of nasal flow through the nose. Nasal 
inspiration correlates most with the subjective feeling of 
obstruction and is the best validated technique for moni- 
toring nasal flow in clinical trials and after nasal provoca- 
tion. In contrast to PNIF, PNEF is less validated and used 
in clinical practice in view of the mucus being blown into 
the peak flow meter and subjective discomfort during 
maximal expiration in patients with mucosal disease [85]. 

Active anterior rhinomanometry (Figure 13) represents a 
physiologic measure of nasal air flow and pressure during 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 18 of 39 

Figure 12 Peak nasal inspiratory flow measurement. 

normal inspiration and expiration. It is considered the 
standard technique for the evaluation of nasal airflow 
resistance, hence providing a functional measure of nasal 
patency. Depending on the position of the probes for 
registration, anterior or posterior rhinomanometry can 
be performed, both being valid techniques. When the 
probe is placed in the mouth, posterior rhinomanometry 
values can be obtained for both nasal cavities together or 
for one nasal cavity when sealing of one nostril. In ante- 
rior rhinomanometry, the pressure-sensing tube is placed 
in one nostril and data represent unilateral pressure and 
flow measures. The anterior rhinomanometry is often 
recommended for its' ease of use. 
3/Acoustic rhinometry 

Acoustic rhinometry is a non-physiologic measure of 
nasal patency, measuring echoes of sound impulses sent 
into one nostril (Figure 14). The measurement provides 
information on the nasal luminal anatomic structures, 
either as a measure of nasal volume over a standard dis- 
tance into the nostril or as the minimal cross-sectional 
area within the nasal cavity. The measurement is per- 
formed in each nasal cavity separately. 

Figure 13 Active anterior rhinomanometry 

Figure 14 Acoustic rhinometry. 

^ J 


1/Peak nasal inspiratory flow 

Description The PNIF meter consists of a device evaluat- 
ing the airflow in liter per minute passing through the 
tube, and an anaesthesia mask sealing the nose and mouth 
in an airtight way during nasal inspiration (Figure 12). The 
anaesthesia mask should have the proper seize, i.e. not too 
large preventing leakage of air, or too small compressing 
the nose with impairment of nasal inspiration. 

The patient is asked to blow the nose first. Then he is 
instructed to exhale maximally, after which the mask is 
placed over the nose and mouth with airtight seal 
around the mouth and nose. The patient is then asked 
to inspire forcefully through the nose with closed lips. 
Lip closure is verified during the PNIF test through 
inspection of lip closure through the transparent 
anesthesia mask in order to prevent the generation of 
false high values. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 19 of 39 

The nasal flow is expressed in liter per minute, and 
consecutive measurements are performed. Taking the 
best of 3 outcomes with less than 10% variation is con- 
sidered to be the best means of expression of the result 

Devices Youlten peak flow meter (Clement Clark Inter- 
national) attached to anesthesia mask. 
Advantages - cheap and portable equipment 

- assistance not required after short training session 
(5 minutes) 

- rapid and easy to use 

- good correlation with subjective feeling of nasal 

Disadvantages - influence of lower airway function 

- cooperation of patient required 

- no unilateral measurement possible 

- impossible in patients with alar collapse during 

2/Anterior rhinomanometry 

Description Rhinomanometry provides a quantitative 
measure of nasal airway resistance. In anterior rhinoma- 
nometry (Figure 13), the patient is asked to blow his 
nose, sits in an upright position and the pressure sen- 
sing tube is placed in one nostril with total seal by tap- 
ing off the nostril or inserting an olive-like device or 
nozzle. The contra-lateral nostril is sealed with either 
tape or olive-like device blocking off nostril. Unilateral 
measurements are being performed, demonstrating any 
asymmetry or abnormality in nasal airway resistance. 

When the measurements are performed before and 
after the application of a nasal decongestant spray, the 
differences in resistance can be attributed to nasal 
mucosal congestion. Data obtained after nasal deconges- 
tion allow the evaluation of anatomical factors influen- 
cing resistance. 

Advantages - specific measurement of nasal resistance 

- information on each nostril separately 

- relatively ease technique 

- not time-consuming 

Disadvantages - relatively expensive equipment 

- equipment not portable 

- operator required 

- impossible in case of total obstruction of one 

- interference with nasal cycle 

- weak correlation with subjective nasal congestion 
3/Acoustic rhinometry 

Description The acoustic rhinometer generates an 
acoustic wave that is transmitted through a tube into 
one nostril (Figure 14). The size and the pattern of the 
reflected sound waves provide information on the 

structure and dimensions of the nasal cavity, with the 
time delay of reflections correlating with the distance 
from the nostril. The conversion of echo measurements 
to nasal volume requires mathematical calculations and 
theoretical assumptions. 

The patient sits in upright position, clears its' nose 
and places the nosepiece into the nostril. The nosepiece 
should fit the nostril, ensuring an airtight seal. Measure- 
ments are performed during breath holding. 

When the measurements are performed before and 
after the application of a nasal decongestant spray, the 
differences in cross-sectional diameter of the nose can 
be attributed to nasal mucosal congestion. Data 
obtained after nasal decongestion allow the evaluation 
of anatomical factors influencing the cross-sectional dia- 
meter of the nose. 
Advantages - easy to use 

- minimal patient cooperation 

- information of each nostril separately 

Disadvantages - non-physiological measure of nasal 

- operator required 

- interference with nasal cycle 

- weak correlation with subjective nasal congestion 

Other techniques 

* Anterior and posterior rhinoscopy Anterior rhino- 
scopy allows the examiner to evaluate the anterior half 
of the nasal cavity, discriminating mucosal from ana- 
tomic disease. The subjective evaluation of nasal patency 
by the appreciation of the endonasal lumen, anatomic 
relationships and mucosal disease is the most important 
diagnostic tool for the evaluation of nasal patency. 

In posterior rhinoscopy, a small mirror is placed in 
the oropharynx behind the soft palate, allowing the eva- 
luation of the choanal openings and mucosal disease at 
the nasopharynx. In experienced hands, this technique 
may be helpful in the diagnosis of posterior nasal dis- 
ease but its' routine use is hampered by a vomiting 
reflex in a substantial portion of patients. As nasal endo- 
scopy allows the full appreciation of the nasal cavity and 
nasopharynx, the diagnostic role of posterior rhinoscopy 
has become restricted to those cases where nasal endo- 
scopy is not available or desired like in young children. 

* Nasal endoscopy (Figure 8) A rigid nasal endoscope 
with 0° or 30° angle is gently inserted into each nostril, 
examining the inferior and middle meatus, nasopharynx, 
septal anatomy and endonasal mucosal state. Due to the 
limited discomfort for the patient, the possibility of 
thorough examination of the nasal cavity and the infor- 
mation on the mucosal condition, nasal endoscopy is 
the gold standard for evaluation of nose in patients with 
sinonasal disease [2]. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 20 of 39 

* Mirror test (Figure 7) Holding a cold metal spatula or 
plate under the nose during expiration allows the exami- 
ner to evaluation the condensation of exhaled air onto 
the metal device. Specific attention is being paid to the 
symmetry of the condensation or unilateral absence of 
condensation. In view of the non-invasive character of 
the test, the rapid, cheap and easy methodology, it can 
be useful as a screening tool for evaluation of nasal 
patency in children. The fact that the expiratory flow 
does not correlate well with the subjective feeling of 
nasal obstruction makes this test of limited diagnostic 
value in the evaluation of nasal congestion. 

Variability and correlation with subjective symptoms 
1/Peak nasal inspiratory flow 

* Variability - PNIF measures may vary from the char- 
acteristics of the flow meter and mask used for analysis. 

- Intra-individual variations may relate to diurnal 
changes, with PNIF values being lower in the morning 
and highest at dinner [85]. 

- Inter-individual variations may relate to subject 
technique, respiratory function, and cooperation. Hor- 
monal changes, microbial and environmental factors 
affecting the nasal mucosal congestion like tempera- 
ture and smoke, may cause changes in PNIF between 

* Correlation between PNIF and nasal obstruction 
symptom A strong positive correlation has been 
reported between PNIF and the subjective feeling of 
nasal obstruction determined by means of question- 
naires [86-88]. This positive correlation was not consis- 
tently found in all studies [89,90]. 

* Variability The nasal cycle interferes with the mea- 
surement of cross-sectional diameter and data should be 
interpreted in this respect. 

* Correlation between rhinomanometry and nasal 
obstruction Ojbective measures of nasal resistance do 
not correlate well with subjective syptoms. Some studies 
however show corresponding results between rhinoma- 
nometry and subjective symptom scoring after inducing 
(de)congestion [91,92]. 

3/Acoustic rhinometry 

* Variability - The nasal cycle interferes with the mea- 
surement of cross-sectional diameter and data should be 
interpreted in this respect. 

- Large inter-individual variations are present. 

* Correlation between acoustic rhinometry data and 
nasal obstruction In healthy individuals, there is poor 
correlation between acoustic rhinometry data and sub- 
jective nasal obstruction scores, whereas correlations are 
better in congested subjects [93,94]. 


Depending on the specific aim of nasal patency and flow 
evaluation, one may rely on different tools for the eva- 
luation of nasal patency and flow. A table with clinical 
use and indicitions is provided below (Table 6). 



The evaluation of the presence of virulent bacteria 
inside the nasal and sinus cavities represents a diagnos- 
tic tool in rhinosinusitis. Although there is no evidence 
for benefit in establishing diagnosis or improving treat- 
ment outcomes by using routine microbiological analysis 
of nasal or sinus samples in uncomplicated acute or 
chronic rhinitis or rhinosinusitis [2], research which was 
focused during the past decade on the role of bacterial 
superantigens, biofilms, response to fungal antigens, 
osteitis and intracellular bacterial growth in nasal and 
sinus mucosa may give rise to broader microbiological 
analysis of samples from nose and sinuses, involving 
new, more sensitive detection techniques. Although 
detection of microbes or their products in the samples 
is highly improved, problems remain with establishing 
relevant microbial pathogenicity, virulence, viability on 
one hand, and relevance of the detected microbes to the 
development of symptoms/disease on the other hand. 

Colonization versus infection 

Rhinosinusitis is defined as inflammation of the nose 
and sinuses and the diagnosis is based on characteristic 
symptoms. The definition does not imply infection as 
the etiological cause. The nasal and sinus cavities and 
nasopharynx are colonized with commensal bacteria, 
but also (especially in children) with those belonging to 

Table 6 Tools for the evaluation of nasal patency and 




Diagnostic purposes 

- unilateral disease 



- correlation with 





Use in children 

2-6 y 



6-18 y 



Provocation studies 




Clinical trials 




Home monitoring 


Evaluation of effect of 





Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 21 of 39 

usually pathogenic strains (like Staphyloccus aureus in 
adults; Streptococcus pneumoniae or Haemophilus 
influenzae in children) [95]. Such colonization does not 
lead to marked inflammatory cell activation or 

In symptomatic patients with clinical evidence of 
infectious rhinosinusitis, the identified pathogen may be 
considered as the cause if it is present in more than 
1000 colony forming units (cfu) per ml (usually more 
than 10.000 cfu. in acute rhinosinusitis), and there is an 
inflammatory response of the host, proved by increased 
number of leukocytes in the samples [96] . 


- to establish indications for microbiological assessment 
of nasal or sinus samples in non-complicated and com- 
plicated rhinitis/rhinosinusitis 

- to define advantages and disadvantages of conven- 
tional culture-based phenotyping of bacteria and moni- 
toring antimicrobial sensitivity, serologic response 
measurements and molecular techniques based on 
detection of proteins or nucleic acid directly or by 

- to find an evidence-based algorithm using different 
microbiological sampling and detection techniques, 
coupled with monitoring of the host response, and ade- 
quate interpretation of the results in terms of distinguish- 
ing between colonization and infection, relevance of 
microbial pathogenicity and virulence for the develop- 
ment of symptoms and impact of detection of microbes 
and their antimicrobial sensitivity on treatment. 


Nasal and sinus samples for microbiological assessment 
are taken as swabs, aspirates, lavages or biopsies. Moni- 
toring of the local host response may be done using 
cytology, biopsy or lavage, or systemically using serol- 
ogy. The poor correlation between nasal/nasopharyngeal 
and sinus swabs suggests that sinus sample contamina- 
tion with nasal or oral cavity colonizing bacteria may 
lead to misinterpretation of the microbiological results. 
To obtain adequate samples, disinfection of the vestibule 
is indicated if the sinus swab or lavage is taken via nasal 
endoscopy or sinus puncture. Maxillary sinus samples 
can be taken through inferior meatal puncture, transoral 
puncture or endoscopically guided through the middle 
meatus. Correlation of endoscopically taken samples 
from maxillary sinuses, compared to maxillary sinus 
puncture is high in most of the studies [97]. 

Routine bacteriological analyses of the samples are 
based on cultivation on selective plates and phenotyping 
and identification of gram positive, gram negative and 
anaerobic bacteria. Processing and the time elapsed 
from taking the samples to cultivating has an impact on 

detection sensitivity, at least for some bacterial strains 
(especially anaerobes). Cultivating is successful in detect- 
ing only viable bacteria and counting the colony forming 
units is relevant for defining significance of bacterial 
growth to symptoms. Different methods of antimicrobial 
sensitivity testing may be applied. 

For the detection of intracellular bacteria, immunohis- 
tochemistry may demonstrate a specific bacterial strain 
in mucosal tissue. Detection and amplification of micro- 
bial RNA and DNA has improved detection sensitivity, 
but does not give information on microbial viability. 
Real-time quantitative polymerase chain reaction (RT- 
PCR) may give information of the number of bacteria, 
but sequential samples are needed to prove viability. For 
the detection of bacteria in biofilm [98], fluorescent in 
situ hybridization (FISH) is usually applied, coupled 
with confocal microscopy. 

Sensitivity and specificity 

The recovery rate in the samples of chronic maxillary 
sinusitis, both aerobic and anaerobic bacteria, varied in 
different studies from 45% to 92%, and is dependent on 
adequate sampling, culture techniques and detecting 
techniques. Although sinonasal bacteria are detected in 
up to 90% of chronic rhinosinusitis patients, their role 
in severity and pattern of inflammation is even less clear 
than in ARS. In a study where bacteria were cultivated 
in 88% of the sinus samples from patients operated for 
CRS, inflammation was confirmed microscopically in 
only 11% [99]. PCR may detect minute amounts of bac- 
terial DNA, which may suggest extremely high sensitiv- 
ity but gives no information on bacterial viability, or 
impact on the inflammation. Quantitative RT-PCR may 
offer information on bacterial count from small samples, 
but its specificity and sensitivity depends on the primers 
used for analysis. In the very few sinusitis studies com- 
paring PCR with conventional microbiology, PCR was 
not found to be more sensitive or specific than cultiva- 
tion techniques [100]. 


There is no evidence that microbiological assessment of 
nasal or sinus samples has any impact on outcomes in 
rhinitis/rhinosinusitis. Although randomized double 
blind placebo controlled trials indicate antibiotic treat- 
ment of ARS is significantly superior to placebo [2], there 
is no evidence that antibiotic treatment based on micro- 
biological sampling gives better outcomes compared to 
empiric antimicrobial treatment in non-complicated 
acute rhinosinusitis. Thus identification of pathogens in 
ARS is not indicated. European guidelines for the treat- 
ment of ARS suggest that ARS non-responsive to empiri- 
cal antimicrobial treatment and topical nasal steroids, as 
well as complicated ARS, should be referred to an ENT 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 22 of 39 

specialist. At that time, further diagnostic procedures 
including microbiology are advised [2] . 


Microbiological assessment is not to be used routinely 
in diagnosis of rhinitis/rhinosinusitis. ARS non-respon- 
sive to empirical antimicrobial treatment and topical 
nasal steroids should be referred to an ENT specialist, 
where further diagnostic procedures, including micro- 
biology, should be done. 

Evaluation of Mucociliary Clearance 


In children with rhinosinusitis presenting with long- 
standing and persistent anterior rhinorrhoea, one may 
be interested in the evaluation of the function of the 
mucociliary clearance system for diagnostic purposes 
[101]. By their coordinated movement, the ciliae lining 
the respiratory epithelium transport the mucus layer 
with entrapped inhaled particles from the nasal cavity 
towards the hypopharynx [102]. In this way, about 10 
ml of mucus is transported daily from the upper air- 
ways towards the hypopharynx, ultimately being swal- 
lowed and cleared from the airways. Normal 
mucociliary transport is essential for the maintenance 
of healthy sinuses. In case of infection and/or congen- 
tial dysfunction of the ciliae like in primary ciliary dys- 
kinesia (PCD) [101], the mucociliary transport is 
inadequately or not taken place. In PCD, lack of muco- 
ciliary transport may lead to chronic rhinosinusitis and 
bronchiectasis. In chronic inflammation, mucostasis, 
hypoxia, microbial products, toxic inflammatory med- 
iators may induce secondary ciliary changes, i.e. sec- 
ondary ciliary dyskinesia (SCD), with inadaquate 
mucociliary transport. 


Objective evaluation of the mucociliary clearance of the 
upper airways in order to quantify the proper function 
of the ciliae of the respiratory epithelium lining the 
upper respiratory tract. 


Mucociliary clearance time 

The mucociliary transport (MCT) mechanism ensures 
the clearance of entrapped particles in the mucus lining 
the nasal mucosa towards the hypopharynx. Several 
non-absorbable substances have been used for the eva- 
luation of MCT in patients. 

The saccharine test evaluates the time a patient needs 
to have a sweet taste after placement of a 1-2 mm parti- 
cle of saccharine on the inferior turbinate mucosa 1 cm 
from the anterior end. The patient has to sit quitely 
with the head bent forward and without sniffing, 

coughing, sneezing, drinking or eating during the 

Alternatively, one can monitor the time needed for a 
dye like methylene blue to be transported from the 
mucosa of the anterior third of the nasal cavity towards 
the hypopharynx. Other substances like technetium- 
99m-labeled iron oxide have also been used. The MCT is 
considered to be normal below 15 minutes, and should 
be less than 1 hour. 

As the MCT can only be measured in cooperative 
patients with patent nasal cavities and in the absence of 
severe mucosal disease, this test has limited diagnostic 
value due to its low sensitivity and specificity. Further- 
more, the test takes a long time and has a high inci- 
dence of false positive and negative results [101]. 
Electron microscopy 

Harvesting epithelial cells is performed by scraping 
along the inferior and middle turbinates by the use of a 
sterile cytology brush. These epithelial cells can be used 
for either structural investigation of the cilia of nasal 
epithelial cells with electron microscopy or for measur- 
ing ciliary beat frequency [103]. 

In primary and secondary ciliary dysfunction, several 
abnormalities can be observed in the dynein structures 
of the epithelial ciliae like total/partial absence of dynein 
arms, aberrant organization of the dynein arms and/or 
disorientation [101]. PCD is associated with the latter 
abnormalities but SCD may also present with these 
structural abnormalities. Therefore, electron microscopic 
evaluation of harvested epithelial cells may aid in the 
diagnosis of PCD, but is not 100% sensitive nor specific. 
Ciliary beat frequency measurement 

Harvested epithelial cells can be evaluated for ciliary beat 
frequency (CBF) and the ciliary wave form analyzed in 
detail by digital high speed video imaging. The evaluation 
of the frequency of the beating of cilia as well as the eva- 
luation of their coordinated movement can be performed 
by computerized programs using a Fast Fourrier analysis. 
Normal values of CBF vary upon the methodology used, 
the age of the patient, and the culture conditions. The 
demonstration of normal CBF and beat pattern excludes 
the diagnosis of PCD. 
Ciliogenesis in vitro 

The evaluation of ciliogenesis in vitro constitutes the gold 
standard for diagnosis of PCD, allowing the differentiation 
between primary and secondary ciliary dyskinesia. A 
biopsy of the nasal mucosa is taken, and nasal epithelial 
cells are dissociated by enzymatic digestion and incubated 
for 6 to 8 weeks until cilia reappear on the apical side of 
the epithelial cells. The new cilia can be evaluated for their 
electron microscopic structure and coordinated activity. In 
PCD patients, no ciliogenesis takes place whereas patients 
with ciliary dysfunction due to infection/inflammation pre- 
sent with properly functioning ciliae after ciliogenesis. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 23 of 39 


No ideal test is available for the diagnosis of PCD. In 
case of suspicion of PCD in a patient with rhinosinusitis 
since birth, familial history of PCD and associated fea- 
tures of Kartagener syndrome, i.e. situs inversus and 
infertility, one should consider diagnostic tests of ciliary 
function by evaluation of CBF, electron microscopic eva- 
luation of the dynein arms of the cilia, and/or evaluation 
of the cilia after ciliogenesis in vitro. As these techni- 
ques are not available in routine ENT practice, one may 
rely on measuring nasal NO levels as low NO levels 
have been associated with PCD and therefore represent 
a good screening tool for PCD (see chapter on NO 

Blood and Additional Tests 


Blood analysis may confirm or refute the definite diag- 
nosis in specific clinical conditions. 


Blood analyses including tests for allergen-specific IgE 
have been dealt with in the section on allergy testing. In 
severe non-infectious, non-allergic rhinitis, one may con- 
sider full blood count, including eosinophils, thyroid func- 
tion, thyroid auto- antibodies, anti- nuclear antibodies, 
extractable nuclear antibodies (anti- Ro and anti-La are 
usually positive in Sjogren's syndrome), pregnancy test or 
tests for drugs of addiction on urine. Sjogren's syndrome 
(SjS) is a relatively common autoimmune disease charac- 
terized by oral and ocular dryness. Patients may present to 
the rhinitis clinic with symptoms of nasal obstruction, dry- 
ness or cough. There is an increasing need for simple, sen- 
sitive and rapid technologies for the diagnosis of SjS and 
other autoimmune diseases. A quick version of luciferase 
immunoprecipitation systems (QLIPS) can now be used to 
produce a rapid, specific and quantitative test to detect 
auto-antibodies associated with SjS. Ro52 was the most 
informative with antibody titers in the Ro52-seropositive 
SjS samples approximately 1000 times higher than in 
healthy controls. Validation of the anti-Ro52 QLIPS test 
showed 66% sensitivity and 100% specificity and has the 
potential to be adapted for point-of-care evaluation of 
patients with SjS and other rheumatologic diseases [104]. 
The need for biopsy looking for lymphocytic infiltration of 
salivary glands should be reduced and in any case is inac- 
curate in elderly patients [105]. 

In case of rhinorrhoea only, especially if unilateral, 
beta2-transferrin should be measured in nasal secretions. 
If present, the secretions are cerebro-spinal fluid and 
reveal a skull base defect. Beta-2 transferrin is a carbohy- 
drate-free (desialated) isoform of transferrin, which is 
almost exclusively found in the CSF- blood or nasal 
secretion does not disturb the test. Beta-2 transferrin is 

not present in blood, nasal mucus, tears or mucosal dis- 
charge. This protein was first described in 1979. Intense 
research over the last decade has validated its characteris- 
tics and value in clinical use as a specific CSF marker 
[106]. Beta-2 transferrin was reported to have a sensitiv- 
ity of near 100% and a specificity of about 95% in a large 
retrospective study. Detection of glucose in the nasal 
sample fluid using Glucostix strips has been a traditional 
method for detection of the presence of CSF in nasal and 
ear discharge. Glucose detection using Glucostix test 
strips is not recommended as a confirmatory test due to 
its lack of specificity and sensitivity. Interpretation of the 
results is confounded by various factors such as contami- 
nation from glucose-containing fluid (tears, nasal mucus, 
blood in nasal mucus) or relatively low CSF glucose levels 
(meningitis). Studies have shown that glucose can be 
detected in airways secretions from people with diabetes 
mellitus, stress hyperglycaemia and viral colds. 

Rhinosinusitis without nasal polyps 

Depending on the clinical history and examination, con- 
sider the following analyses: 

* full blood count including differential white cell 
count, ESR and/or C Reactive Protein, 

* evaluation of renal, liver and thyroid function 

* humoral immunity markers: immunoglobulins, IgG 
subclasses, specific antibody levels to tetanus, haemophi- 
lus, pneumococcus and response to immunization if 

* cellular immunity markers: T and B cell numbers 
and ratios 

* HIV status. 

* Angiotensin converting enzyme (ACE) is usually up- 
regulated in macrophage activation in diseases such as 
sarcoidosis and tuberculosis. Of note, the following diag- 
nostic tests aided to diagnose ocular sarcoidosis [107]: 
negative tuberculin skin test in a BCG-vaccinated patient 
or in a patient having had a positive tuberculin skin test 
previously, elevated serum angiotensin converting 
enzyme (ACE) levels and/or elevated serum lysozyme, 
chest x-ray revealing bilateral hilar lymphadenopathy 
(BHL), abnormal liver enzyme tests, and chest CT scan 
in patients with a negative chest x-ray result. 

* c-ANCAs (anti- neutrophil cytoplasmic antibodies) 
are raised in Wegener's granulomatosis, in 60% of 
patients where upper respiratory tract alone is involved. 

Rhinosinusitis with nasal polyps 

Some specific pathologic entities should be considered 
in severe nasal polyp disease and require additional 

1/Churg Strauss syndrome(CSS) 

ANCAs are present in approximately 40% of patients 
with CSS. A pANCA pattern with specificity for MPO is 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 24 of 39 

found in most ANCA-positive patients. ANCA positivity 
is mainly associated with glomerular and alveolar capil- 
laritis [108]. 

Antineutrophil cytoplasmic antibodies (ANCA) are 
predominantly IgG autoantibodies directed against con- 
stituents of primary lysosome granules of neutrophils 
and monocytes. Several antigenic targets exist: those 
ANCA directed to proteinase 3 or myeloperoxidase are 
clinically relevan. The importance of other ANCA 
remains unknown. Both are strongly associated with 
small vessel vasculitides, including Wegener's granulo- 
matosis, microscopic polyangiitis, and Churg-Strauss 
syndrome, and the localised forms of these diseases (eg, 
pauci-immune necrotising and crescentic glomerulone- 
phritis). ANCA is a useful serological test to assist in 
diagnosis of small-vessel vasculitides. 85-95% of patients 
with Wegener's granulomatosis, microscopic polyangii- 
tis, and pauci-immune necrotising and crescentic glo- 
merulonephritis have serum ANCA [109]. Besides their 
diagnostic potential, ANCA might be valuable in disease 
monitoring, although the ESR is quicker. 

Recent data seem to confirm the long-disputed patho- 
genic role of these antibodies: myeloperoxidase-ANCA 
are directly involved in the pathogenesis of necrotizing 
vasculitis. This is less clear for proteinase 3-ANCA, 
markers for Wegener's granulomatosis. Complementary 
proteinase 3, a peptide translated from the antisense 
DNA strand of proteinase 3 and homologous to several 
microbial peptides, may be involved in induction of pro- 
teinase 3-antineutrophil cytoplasmic autoantibodies. 

A strategy based on screening for ANCA with ELISA 
or fluoroenzymeimmunoassay (FEIA) without prior 
indirect immunofluorescence (IIF) is a valuable alterna- 
tive to screening with IIF and confirming with ELISA or 

Cocaine-induced midline destructive lesions unfortu- 
nately have a high prevalence of cytoplasmic antineutro- 
phil cytoplasmic antibodies, limiting this test's 
usefulness in distinguishing this disorder from Wege- 
ner's granulomatosis [110]. 
2/Aspirin sensitivity 

The aspirin provocation test, considered to be the gold 
standard in the diagnosis of aspirin sensitivity, may be 
associated with severe adverse reactions; thus, alternative 
procedures with a higher safety profile are highly desir- 
able. Although the cellular antigen stimulation test 
(CAST) has been proposed as an alternative a recent 
study using CAST to measure cys LTs pre and post 
challenge showed that although the leukocytes of 
patients with aspirin sensitivity produce higher amounts 
of Cys-LTs as measured by CAST the assay had a sensi- 
tivity of 25%, a specificity of 92.3%, and positive and 
negative predictive values of 28.7% and 90.7%, respec- 
tively. The low sensitivity and predictive values limit the 

clinical usefulness of this test in the diagnosis of aspirin 
sensitivity [111]. 
3/Fungal sinusitis 

Fungal spores are continuously inhaled and deposited 
on the airway mucosa, both in healthy persons as well 
as in patients with CRS. Five forms of fungal disease 
affecting the nose and paranasal sinuses have been 
recognized [112]: 

(1) acute invasive fungal rhinosinusitis (including rhi- 
nocerebral mucormycosis), 

(2) chronic invasive fungal rhinosinusitis, 

(3) granulomatous invasive fungal rhinosinusitis, 

(4) fungal ball (mycetoma), and 

(5) non-invasive (allergic) fungal rhinosinusitis. 
There are several potential deficits in the innate and 

potentially also acquired immunity of CRS patients that 
might reduce or change their ability to react to fungi. 
There are not many arguments to suggest a causative 
role for fungi in CRS with or without nasal polyps. 
However, due to the intrinsic or induced change in 
immunity of CRS patients, fungi might have a disease- 
modifying role. 
4/Primary ciliary dyskinesia 

Congenital dysfunction of the mucociliary transport sys- 
tem, called primary ciliary dyskinesia (PCD) is a rare heri- 
ditary condition, associated with dextrocardia and 
infertiliy. The discrimination between PCD and secondary 
dysfunction of the cilia due to microbial or environmental 
agents, is crucial for the diagnosis. Several diagnostic tools 
are available. Determination of the mucociliary clearance 
time is a non-invasive, cheap and rapid diagnostic tool, 
with relatively low sensitivity and specificity. Nasal NO is 
reported to be very low in patients with PCD [113] in con- 
trast to CRS, NP and other nasal inflammatory conditions. 
Therefore, nasal NO measurement represents a valuable 
screening tool for PCD. Electron microscopic evaluation 
of the epithelial cilia may provide additional hints for the 
diagnosis without being 100% specific or sensitive [114]. 
The definite proof of PCD comes from epithelial cell cul- 
tures and of ciliogenesis in vitro [115]. However, the time- 
consuming and costly nature of this investigation limits 
its' use as a screening tool. 
5/Cystic Fibrosis (CF) 

The diagnosis of CF is suspected in case of severe CRS 
with NP and thickened secretions, hypoplasia of the para- 
nasal sinuses, in association with recurrent broncho-pul- 
monary infections. CF is an autosomal recessive disease 
caused by mutations in the the CF transmembrane con- 
ductance regulator (CFTR) gene that results in abnormal 
viscous mucoid secretions in multiple organs and with 
rhinosinusitis as one of the clinical features beside endo- 
bronchial infections and pancreatic insufficiency. 

Blood analysis for CFTR gene mutations may demon- 
strate homozygote and heterozygote gene mutations in a 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 25 of 39 

subgroup of CF patients [116]. CT scans of the parana- 
sal sinuses may show features associated with CF: hypo- 
plasia of the frontal and/or sphenoidal sinuses, full 
opacification of most sinonasal cavities, and pseudomu- 
cocoeles in the maxillary sinuses with medialization of 
the lateral nasal wall. 

The sweat test remains the gold standard for diagnosis 
of CF, as it is non-invasive, cheap and painless, with 
high sensitivity and specificity. 


* Blood analysis may be an alternative for skin prick test 
in patients suspect of allergic rhinitis. 

* Specific patients with non-allergic, non-infectious 
rhinitis may require the following analyses: full blood 
count, including eosinophils, thyroid function, thyroid 
auto-antibodies, anti- nuclear antibodies, extractable 
nuclear antibodies in Sjogren's syndrome, pregnancy test 
or tests for drugs of addiction on urine. 

* In specific cases of rhinosinusitis without NP the fol- 
lowing analyses are recommended: 

* full blood count including differential white cell 
count, ESR and/ or C Reactive Protein, 

* evaluation of renal, liver and thyroid function 

* humoral immunity markers: immunoglobulins, IgG 
subclasses, specific antibody levels to tetanus, haemophi- 
lus, pneumococcus and response to immunization if 

* cellular immunity markers: T and B cell numbers 
and ratios 

* HIV status. 

* Angiotensin converting enzyme (ACE) 


Imaging in Rhinology 


Imaging of the nose and sino-nasal cavity is used as an 
objective diagnostic tool in establishing the diagnosis 
and in staging the severity of rhinosinusitis (RS) and 
nasal polyposis (NP). The diagnosis of RS with/without 
NP is based on the presence of characteristic clinical 
symptoms, which are confirmed by either nasal endo- 
scopy or radiographic imaging [2]. Computerized tomo- 
graphy (CT) scans provide substantial information about 
paranasal sinus anatomy and are mandatory for safe 
endoscopic sinus surgery. Unlike standard X-ray and 
ultrasonography (USG), CT scans of the sino-nasal cav- 
ity and magnetic resonance imaging [117] provide objec- 
tive information on the extent of sinus disease and are 
the most frequently used objective tools in staging of 
severity of the disease (with the exception of endoscopic 
staging of polyp size). For evaluation of the bony anat- 
omy and discrimination of the sino-nasal cavities. 


The aims of radiologic imaging are the demonstration of 
the source of individual sino-nasal symptoms, the extent 
of the sinonasal disease, the relation of the sinonasal 
problem with surrounding structures and the evaluation 
of the sinonasal anatomy prior to sinus surgery. 


Plain film radiographs in standard projections (Caldwell 
and Waters frontal views and Rhese oblique view) provide 
little information on disease extent and no information on 
sinus anatomy. They do provide some information on the 
size of the sinuses and air content in the maxillary and 
frontal sinuses, but discriminate poorly between bone, 
mucosa and secretion compared to CT or MRI and may 
be misleading in diagnosis, and dangerous in surgery. 
Therefore, plain X-ray radiographs are not advised in rou- 
tine rhinology clinic. In children with clinical suspicion of 
adenoid hypertrophy being responsible for nasal obstruc- 
tion, lateral plain X-ray images (Figure 15) may show the 
adenoid hypertrophy and be of help in the therapeutic 
approach in these children. 

Following the introduction of CT scans in the 1970s and 
the concepts of functional endoscopic sinus surgery 
(FESS) in the 1980s, CT scanning has become the most 
important imaging modality and helped the development 
of endoscopic surgery of the sinuses and skull base. The 
new multi-detector CT (MDCT or MSCT) scanners (4th 
generation CT scanners) have achieved very short radia- 
tion exposure time, taking scans in one cycle, using spiral 

Figure 15 Plain X ray of skull allowing the evaluation of the 
adenoid volume in relation to the nasopharyngeal airway 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 26 of 39 

mode, instead of two projections used in previous genera- 
tions, which was more time consuming, and uncomforta- 
ble for some patients. They also enable multi-planar 
reconstructions, even in curved planes, like a reconstruc- 
tion of orthopantomography of the upper jaw and allow 
precise coronal, axial, sagittal and various 3D reconstruc- 
tions as well as virtual endoscopy. The MDCT scanning 
should be done at 3 mm contiguous slices or less through- 
out the 3 planar scans using both wide («bone») and nar- 
row («soft-tissue») window settings. Such reconstructions 
are useful in surgical planning, but are not needed for sta- 
ging. Low-dose protocols should be applied, taking into 
account the potential pathology. Although new software 
packages enable 3D reconstructions and virtual endo- 
scopy, besides being time consuming, such images cannot 
replace surgeons' preoperative analysis of the scans in 3 

Coronal sections have been the most requested plane 
on CT imaging of the nose and sinuses as this closest 
resembles the surgical anatomy encountered in endo- 
scopic sinus surgery, presenting ostio-meatal complex 
(unit) and relationship between sinuses, orbit, and skull 
base (Figure 16). Axial sections may be required to 
visualize the anterior and posterior walls of the sinuses. 
Reconstruction of MSCT scans in coronal, axial and 
sagittal planes, enable excellent surgical planning 

Although more time consuming and costly, the use of 
MRI is recommended in patients with complicated inflam- 
matory sinus disease extending beyond the boundaries of 
the sinonasal cavities and/or in patients with suspected 
neoplasms. Tl, T2 and STIR protocols are used, enabling 
superior resolution to CT on the interfaces between 

mucosal lining, dura, fat and secretions, but CT and MR 
present complementary techniques for imaging in these 
unique circumstances. Contrast-enhanced high resolution 
SE axial and coronal Tl-WI further differentiate soft tissue 
structures and intracranial and/or intra-orbital extension 
of pathology can be better demonstrated in this manner. 
Although there is no ionizing radiation, allowing MRI to 
be repeated, certain contraindications for its use should be 
considered such as metal objects, prosthesis and implants, 
e.g. cardiac pacemaker, implanted cardiac defibrillator, 
aneurysm clips, carotid artery vascular clamp, neurostimu- 
lator, insulin or infusion pump, implanted drug infusion 
device, bone growth/fusion stimulator, cochlear, otologic, 
or ear implant. The duration and methodology of MRI 
can cause claustrophobia. 

Ultrasonography of the paranasal sinuses is easily 
available, cheap and quick, with no irradiation or dis- 
comfort involved. Ultrasonography offers an opportunity 
for repetitive examination, which might be important 
for the follow-up in evolution of acute rhinosinusitis. 
Sensitivities have been reported from 29% to 100% and 
specificities from 55% to 99%, but limited to analysis of 
maxillary and frontal sinuses. However, it provides little 
information on disease extent. 

Sensitivity and specificity 

The diagnosis of rhinosinusitis is largely based on the 
patient's history, with radiologic imaging confirming the 
clinical diagnosis of RS. It is impossible to differentiate 
between acute and chronic rhinosinusitis based on ima- 
ging. CT scan is not indicated as a diagnostic procedure 
in acute rhinosinusitis, except when a complication is 
suspected or recurrent rhinosinusitis is not responsive to 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 27 of 39 

treatment. As CT and MRI are sensitive enough to detect 
changes in the paranasal sinuses of asymptomatic indivi- 
duals, it is also important to realize that a significant por- 
tion of asymptomatic patients show abnormalities on CT 
scans [2]. 

When comparing concordance between endoscopy and 
CT staging in rhinosinusitis, the correlation was 65% for 
positive and 71% for negative results [118]. The various 
staging systems have been used to judge the severity of 
rhinosinusitis based on extent of the inflammatory dis- 
ease within the paranasal sinuses. Most of the CT staging 
systems tried to divide severity into 4 grades or 4 stages 
(Kennedy, Levine and May, Friedman, Harvard). How- 
ever, validation studies of the different staging systems 
have shown that a simple scoring system such as the 
Lund-Mackay score would better quantify severity of the 
disease, although no system currently available allows 
clinicians to judge the evolution of this disease or to indi- 
cate prognosis [119]. The Lund Mackay system is based 
on scoring each sinus with 0-2 points (0- no pathology, 1 
point any partial opacity, 2 points- total opacity), giving a 
score of 0-12 per side. However, even this system does 
not result in significant correlation with symptom sever- 
ity scores. Normal Lund-Mackay score for adults is 4.26 
(95% CI, 3.43 to 5.10) [120] and for children it is 2,81 
(95% confidence interval, 2.40 to 3.22), with only 19,3% 
having a score of 0 [119]. 

The accuracy of CT in the diagnosis of CRS was tested, 
comparing CT scores with histopathologic grade of 
inflammation and compared to a control group without 
rhinosinusitis utilizing well designed criteria. By using the 
ROC method, the sensitivity of CT was found to be 94% 
and specificity 41% using Lund score cut-off value for RS 
greater than 2, while putting it at the level of incidental 
Lund scores (above 4) increased specificity to 59%. Using 
the same method in pediatric rhinosinusitis, the same 
author found, using a Lund score cut off of five to repre- 
sent true disease, sensitivity of the CT at 86% and specifi- 
city 85%. Lund scores of two or less have an excellent 
negative predictive value, and Lund scores of five or more 
have an excellent positive predictive value, strongly indi- 
cating true disease. 

Plain sinus radiographs have shown poor sensitivity 
and specificity, so that even low irradiation does not 
justify its' use. In the studies comparing plain sinus 
radiographs with sinus CT scans, the sensitivity of plain 
film radiography ranged from 36.7 to 66.4% depending 
on localization, while specificity was high (90% and 
over) with the exception of the maxillary sinus (82%) in 
one study. The other study has confirmed better match- 
ing of the CT scans with plain sinus radiographs for 
maxillary sinusitis (78%), but only 52% for the ethmoids 


CT scans remain the gold standard for diagnosis of rhi- 
nosinusitis and for pre-operative evaluation of the sino- 
nasal anatomy. CT scoring has been used to show 
improvement in different treatment studies in ARS and 
CRS but the correlation of the symptom improvement 
rate with CT score improvement rate was often not sig- 
nificant. Due to the radiation dose, CT score improve- 
ment cannot be used as an outcome measure for ethical 
reasons. As a good correlation between scores on CT 
and MRI has been shown, MRI might be a more appro- 
priate imaging outcome. MRI is useful for diagnosis and 
follow-up of patients with benign (eg inverted papil- 
loma) or malignant (eg adenocarcinoma) sinonasal 


There is no evidence to support the use of imaging in 
uncomplicated acute rhinosinusitis. In contrast to ARS 
where CT scans are not mandatory for diagnosis, CT 
scans may confirm the clinical diagnosis of CRS. The 
use of CT scans in 3-dimensional views are highly 
recommended as a roadmap for endoscopic sinus sur- 
gery in order to define specific anatomic relations in the 
individual patient. 

Plain sinus radiographs have low informative value as 
is the case for ultrasonography, both being characterized 
by low sensitivity, but somewhat better specificity in 
maxillary and frontal sinusitis. 

Diagnosis of Occupational Rhinitis 


The diagnosis of occupational rhinitis (OR) is based on 
very careful and detailed medical history and history of 
exposure conditions at work [122]. The purpose of the 
clinical history is to confirm the existence of rhinitis 
and to evaluate it's the link to work. Because often the 
diagnosis of OR have substantial financial and work- 
related consequences, the relationship with the work 
exposure needs to be ascertained with provocation tests 
[122]. A distinction is made on rhinitis caused by agents 
in the working environment, i.e. OR, and rhinitis exacer- 
bated by the work environment, i.e. work-exacerbated 
rhinitis (Figure 17). 

Symptoms and medical history 

The medical history should include the information 
about the exposures at work and their potential capacity 
to cause sensitization or irritate the nasal mucosa. This 
information is normally asked from the employer. Any 
chemicals and proteins that can be sensitizers or irri- 
tants should be recorded. How they are used and what 
is the protective measure at work should be recorded. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 28 of 39 

Work-related rhinitis 

by work 


by work 

Rhinitis (WER) 


* Allergic OR (with latency period): 

• IgE-mediated 

• Non-lgE-mediated 

* Non-allergic OR (without latency): 

• Single exposure: RUDS 

• Multiple exposures: Irritant- 
induced OR 

• Corrosive rhinitis 

Figure 17 Occupational vs work-exacerbated rhinitis. 

Patients should be asked about the time of the exposure 
starting, how long it has lasted and what is the exposure 
level and time of exposure daily and weekly. The rela- 
tion of the symptoms to work and the alleviation of 
them when away from the work are important clues to 
diagnose OR. The typical symptoms are rhinorrhoea, 
sniffing, nasal stuffiness and nasal itch as in any allergic 
rhinitis but even one of these symptoms can be present, 
especially if the exposure has continue long. Often nasal 
stuffiness is the main symptom and rhinorrhoea and 
sneezing often subsides when the exposure continues 
longer timer. Patients can have hoarseness and cough- 
ing, even asthma symptoms during the work hours as 
well. It is relevant to ask when the patient first time was 
treated by physician because of rhinitis symptoms and 
also exclude other reasons for rhinitis like sinusitis and 
seasonal or perennial allergy. 

Examinations and immunological tests 

A routine ENT examination including nasal endoscopy 
should be performed. Skin prick test and/or specific IgE 
tests for common aeroallergens and work related aller- 
gens and chemicals are mandatory. Common aeroaller- 
gens are tested to exclude their role and show if the 

patient is atopic already. It is know that atopic patients 
have more symptoms and are easier sensitized to new 
allergens. SPT are considered to be positive when the 
mean wheal diameter is exceeds 3 mm (area > 7 mm). 
Positive immunological test may appear in a substantial 
proportion of exposed asymptomatic individuals. On the 
other hand, a negative test result makes the diagnosis of 
OR unlikely, provided that appropriate allergens have 
been tested. The main limitation of immunological tests 
in the investigation of occupational allergy results from 
the lack of standardized, commercially available extracts, 
especially low molecular weight agents [122]. 

If lower airway symptoms like cough, wheezing, dys- 
pnoea or diminished ability for physical strain exist, 
additional spirometry and other examinations to exclude 
asthma are needed. In addition, use of any medication 
and other airway or systemic diseases possibly relating 
to the symptoms should be recorded. 

Nasal and inhalation challenge tests 

Both nasal as well as bronchial challenge tests can be 
applied for the diagnosis of OR (Figure 18). Nasal chal- 
lenge tests are the standard diagnostic tool to confirm 
the causative role of a specific agent in the development 
of rhinitis symptoms. Nasal provocation testing repre- 
sents an essential tool in the diagnosis of allergic OR 
but needs to be evaluated in the context of the medical 
and work history and sensitization stat [123]. Several 
methods of exposure of one or both nostrils are being 
reported: throw dropping or spraying and solid agents 
by direct application, by special devices or by sniffing. 
Inhalation challenge (IC) tests are rarely reported to be 
used in the diagnosis of OR, but represent a valuable 
method in the simultaneous evaluation of patients with 
both lower and upper airways symptoms [124]. Even IC 
is resource-intensive methodology, the evaluation of 
nasal and bronchial reactions together save time and 
expenses compared to organization of multiple indivi- 
dual challenges [125]. 

There are no uniformly accepted criteria for the eva- 
luation of nasal challenge reactions. In addition the test 
can be performed either unilaterally or bilaterally. Var- 
ious symptoms and findings scoring criteria based on 
clinical findings or patient symptoms have been tradi- 
tionally used as the main criteria of the positivity of 
nasal challenge reactions. For example the sneeze count, 
inspected nasal blockage (congestion), itching or burn- 
ing of the nose, palate or throat and lacrimation have 
been used 48 or symptom score of nasal itching, sneez- 
ing, and rhinoscopic nasal obstruction, rhinorrhea, and 
mucosal oedema [126]. In addition to the scoring cri- 
teria objective instruments like acoustic rhinometry and 
anterior rhinomanometry are used. Minimum cross-sec- 
tional area of the nose [127] and nasal volume from 2-5 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 29 of 39 

Clinical and occupational history 
Nasal examination 

Immunological tests 

(skin-prick tests and/or specific IgE antibodies) 

Not available 

(e.g. LMW agents) 


(e.g. HMW agents) 


According to 
clinical history 


Nasal provocation test in the 

According to 
required level 
of diagnostic 
conf clence 



Not feasible 

According to 
clinical history 


Workplace assessment of: 

Nasal patency 
Nasal inflammation 
Nonspecific hyperresponsiveness 




Figure 18 Diagnostic algorithm for occupational rhinitis. 

cm depth have been used for evaluation of nasal mucosa 
reactions [128]. In addition nasal peak inspiratory flow 
as well as optical rhinometry and rhinostereometry have 
been introduced for the evaluation of nasal provocation 
results. Measurement of secretion has been introduced 
as one objective and relevant measurement of nasal pro- 
vocation test, and that in a unilateral test it has shown 
to be slightly superior to acoustic rhinometry and rhino- 
manometry [129]. Sham provocation tests should be 
used to confirm the positive reaction with occupational 
exposure and exclude general nasal hyperreactivity. 


The diagnosis of occupational rhinitis is based on the 
patients' history. Allergic OR should be dealt with diag- 
nostically like any other allergic rhinitis, whereas non- 
allergic occupational disease requires more specific 
attention. In case of important socio-economic impact 
of the diagnosis of OR, the diagnosis can be confirmed 
by provocation tests that need to be performed in a 
standardized way involving subjective as well as objec- 
tive evaluation of inflammation. 

Future Tools 

We are dealing with complex diseases in Rhinology and 
need a systems biological approach that could spell the 
end of clinical and basic science as independent research 
fields. Why do patients with the same sensitization pre- 
sent with such a variety of symptoms or why are some 
patients sensitized only for house dust mite or grass pol- 
len, while yet others are sensitized for both? Are we look- 
ing at a single disease with different levels of expression 
or should we consider that these individuals suffer from 
similar, yet different diseases? There are a large number 
of chronic rhinosinusitis patients who may all suffer from 
the same disease or from different disease modalities that 
have a similar symptomatology. Clinical or basic scientific 
conclusions drawn from an inhomogeneous group of 
patients may misinterpret the molecular mechanisms or 
the clinical symptomatology of the disease under 

From a clinical point of view it may seem that the 
healthy individual is probably the least interesting to 
study except as a control in all good studies, but hardly 
ever as the prime focus of research. This practice needs 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 30 of 39 

to be re-examined. It is very important to understand the 
normal healthy response and compare this response to 
the aberrant response in an allergic individual. In the 
case of the immunologic response this concept would 
lead to a number of states of the immune system that 
would also depend on whether we look at a healthy or a 
diseased individual. Moreover, these differences would 
not only be there at the tissue level, but also at the pro- 
tein expression pattern level in individual cells. 

We therefore need to re-evaluate our research tools. In 
hypothesis-driven research we investigate the role of one 
or a limited number of players on a complex disease pro- 
cess, limiting our powers of observation. New analysis 
tools may allow us to analyse a disease in a single indivi- 
dual. However this will mean that we need to collect 
many data points for a single patient, in contrasts to the 
present custom of collecting a few data points for many 
patients. Fortunately, any of the "omics" techniques 
(genomics, transcriptomics, or proteomics) allow this 

Genetics, transcriptomics, and proteomics are tradi- 
tionally seen as three complementary and equivalent 
research fields in that each addresses a different part of 
the information highway. An important realization is that 
both the diseased and the healthy state is a complex 
interplay between a large number of factors that influ- 
ence each other. The transition from healthy to diseased 
state could affect only a small proportion of the factors 
defining the healthy state, but current data suggest that 
differences are rather large. This is most clearly seen 
when the healthy and diseased states are compared at the 
tissue level. The question arises how the two states can 
change from one to the other. Due to the inherent pre- 
sence of negative and positive feedback loops, a network 
is often very resistant to change. It may accommodate 
small changes, but large deviations from equilibrium may 
require more than one defect in network components. 
There are likely to be multiple different combinations of 
defects yielding a similar change from baseline. When a 
disease is studied by looking for defects on a genome 
wide level, we might run into the problem that although 
we study a single disease that the multitude of different 
combination of factors involved would introduce such a 
large mix that statistics may not be able to identify indivi- 
dual factors. At the moment it would seem that (A) a lot 
of factors have been reported to be affected and that (B) 
none of the factors are specific for the disease and are at 
best found enriched in the diseased population. Although 
impractical (one would need to include too many well- 
defined patients), the different studies into genetics 
should also consider previously collected data on other 

This particular problem does not arise when proteomics 
or transcriptomics is used, as the expression pattern will 

define the disease even though the underlying reasons for 
the change into the diseased state might be different. This 
last point is again one of the two biggest problems. The 
disease can be well-described using proteomics and tran- 
scriptomics, but now we will find it hard to define the 
mutation responsible for the diseased state. A concept that 
has not yet been put to the test would combine the best of 
both worlds; use transcriptomics and proteomics to define 
the disease and then focus the mutation analysis specifi- 
cally on the genes/proteins that are found affected. This 
would reduce the number of genes to screen down to a 
more manageable level, so that perhaps even interactions 
between mutations in different genes would become feasi- 
ble. A second down-side of transcriptomics and proteo- 
mics is in the selection of material that will be studied. 
Given the concept of systems biology it would be tempting 
to investigate diseased versus healthy tissue samples, but 
this comes at a price. Firstly, it is not always clear what 
needs to be compared. In the case of chronic rhinosinusitis 
one might question if healthy turbinate would be useful in 
the comparison with nasal polyps as, firstly, they are not 
identical structures and, secondly, they are found at differ- 
ent locations within the nasal cavity. Even when compar- 
able tissues can be found (eg. turbinates of allergic and 
healthy individuals) transcriptomics and proteomics would 
also measure differences in tissue composition. Techni- 
ques that would take this into account are struggling to 
discriminate between changes in expression in a given cell 
and difference caused by differences in numbers of these 
cells between diseased and healthy tissues. Focusing on a 
single cell type would eliminate this problem, at the cost 
of a less comprehensive overview of the systems biology 
and the unknown consequences on expression patterns in 
cells that have been isolated and as a consequence have 
been taken out of their normal tissue environment. 

Dealing with complex data 

After all the clinical and molecular data have been col- 
lected, there is a long list of matters that differ between a 
healthy and a diseased individual. We could analyze the 
items on the top of the list that have changed the most in 
more detail, but it would seem to defeat the point of col- 
lecting all data in the first place. We do not know whether 
items that change the most, are also the most important 
in the disease process. A number of analytical tools exists 
that can help our understanding [130]. The first tool helps 
us to define what causes the variation in all the data we 
have collected. Principal component analysis lists these 
causes in order of their contribution. An example from 
our own epithelial work in allergic rhinitis shows that the 
diseased state (the difference between healthy and allergic) 
is the most important component, followed by differences 
between healthy individuals [131]. This reminds us again 
that we are all clearly different, but also shows that the 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 31 of 39 

allergic individuals resemble each other more strongly. 
Interestingly, this approach could also be used as a diag- 
nostic tool as the location in the plot could identify the 
individual as either diseased or healthy. Moreover should 
we have labelled an individual incorrectly, this would not 
have affected the outcome as individuals are separate data 
points in the graph and need not to be grouped before- 
hand for this analysis. 

The second tool is network analysis showing how the 
factors we have identified interact together. Using data 
from literature it either groups the items on the basis of 
previously reported physical interaction or on reported 
effects of one item on the expression pattern of another. 
Again from our own work on the effect of house dust 
mite allergen on nasal epithelial cells we derive a tran- 
scription regulation model [131,132]. This can be com- 
bined with a clustering tool that describes the expression 
behaviour of genes. At this last level we can think of 
interfering with the disease as the type of expression pro- 
file in a cluster might represent an essential behaviour to 
deal with the diseased state. Understanding the regula- 
tion of such a cluster of the transcription factor level, the 
signal transduction level, or the recently identified micro 
RNA level, could lead to the identification of new targets 
for treatment. 

Concluding Recommendations 

In the following table (table 7), recommendations for each 
diagnostic tool which has been revised are summarized. 


We need to merge all available data into one big model 
of reality. The second important issue is that we need to 
be very strict in our patient selection as failure to do so 
will yield confusing data or alternatively focus on a sin- 
gle individual as if he or she has unique disease, and 
then try to cure this disease for this individual. The uni- 
fication of clinical and basic scientific research has 
started and will be with us for some time to come. 


Different Tools to Assess Sense of Smell 

University of Pennsylvania Smell Identification Test (UPSIT) 

Method: The UPSIT test is a rapid and easy-to-adminis- 
ter method to quantitatively assess human olfactory func- 
tion [133]. The UPSIT shows a high test-retest reliability 
and scores on this test are strongly correlated with the 
detection threshold for phenyl ethyl alcohol in the same 
individuals. When the UPSIT is administered in the stan- 
dardized manner, clinical subjects show a high degree of 
uniformity in UPSIT performance when tested in differ- 
ent laboratories. The 40-odorant UPSIT is used in over 
1500 clinics and laboratories throughout the United 
States, Canada, South America, and Europe, and has 

been administered to nearly 200,000 people since its 
development in the early 1980s. Hundreds of published 
papers have employed this test in academic, clinical, and 
industrial settings. A particular strength of this test is 
that it provides an olfactory diagnosis based on compar- 
ing the patient's test score with normative data, providing 
a percentile score of an individual relative to his or her 
age-matched normal group. Furthermore, a clinician can 
distinguish patients with a normal sense of smell ("nor- 
mosmia") from those with different levels of reduction 
("mild, moderate and severe microsmia") or loss ("anos- 
mia"). The test can also distinguish "probable malin- 
gerers" from those with true olfactory deficits. 

The test consists of four booklets, each containing 10 
odorants with one odorant per page. The stimuli are 
embedded in 10-50 (mu) diameter plastic microcapsules 
on brown strips at the bottom of each page. Above each 
odorant strip is a multiple-choice question with four 
alternative words to describe the odour. The subject was 
asked to release the odorant by rubbing the brown-strip 
with the tip of a pencil and to indicate which of four 
words best describes the odour. Thus each subject 
received a score out of 40 possible correct answers. 

Test-time: 15 min. 

Test-retest reliability: r: 0.981. 

Country: USA 
Conneticut Chemosensory Clinical Research Center Test 

Method: The CCRC consists of two tests of olfactory 
performance [134]: an odour identification task and the 
determination of the n-butanol threshold. Presentation 
of odorants for threshold testing is performed by means 
of a plastic squeeze bottles while odour identification is 
assessed by means of sniff bottles (bottles made of 
glass). The highest concentration of butanol in the series 
was 4% in water; 11 successive dilutions were estab- 
lished as a geometric series dilution ratio of 1:3. Testing 
was performed with the concentrations in ascending ser- 
ies using a two-alternative, forced choice paradigm by 
which patients have to identify the odorant containing 
bottle after both odorant and blank have been adminis- 
tered (double-alternative, forced choice paradigm). The 
threshold was defined as the concentration at which 
subjects correctly identify n-butanol in five successive 
trials. The odour identification task employed eight 
items (baby powder, chocolate, cinnamon, coffee, moth- 
balls, peanut butter, ivory soap and Vicks Vaposteam). 
Patients were given a list with 16 terms comprising 
eight terms describing the items used in the test and 
eight items describing other common items. All odor- 
ants were handled most carefully; the experimenters 
always wore deodorized disposable cotton gloves. Mea- 
surements were performed in quiet, well-ventilated 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 32 of 39 

Table 7 Recommendations for diagnostic tools in rhinoloy 





Evaluation of 

* patients' symptoms and symptom 

strvtrl I ly 

* co-morbidities and general medical 

* medical/surgical history 

* exposure to allergens/irritants 

* cigarette smoke 

* Persona 

* f~li loctirin np i rcic: 
^uctjjLIUI ii I a 1 1 ci 

Essential part of diagnostic process 
In all patients with nasal problems.... 

ann in thrice* \A/itn \c\\Mf^r rf^cniratorx/ XfTtrt Hicpacizi] 
ai \u hi li iujc vvilii luvvtri i trsun a lui y licila uiocast:! 


Evaluation of the impact of nasal disease 

* quality of life 

* different domains of physical and 
mental functioning 

* Generic 

* Disease-specific 

Helpful in clinical practice and clinical trials 



Evaluation of the 

* external and endonasal anatomy 

* endonasal mucosa and lumen 

* Inspection 

* Palpation 

* Ant. and post, 

* Nasal endoscopy 

* Non-ENT doctors should examine the nose including ant. 

* A nasal endoscopy is recommended in 
chronic rhinologic disease 


Evaluation of the sensitization state, 
including the demonstration of the 
specific sensitization state 

* Skin prick test 

* Blood analysis with 
allergen-specific IgE 

Recommended in all patients with clinical suspicion of 
allergic AW disease 



Evaluation of the response of the nasal 
mucosa to 

* allergens 

* aspirin 

* occupational agents 

Provocation by 
inhalation, spray, nasa 
drop or discette 

Recommended in case of doubt about sensitization 


Evaluation of the smell capacity 

Different tests are 
currently available 

Recommended in case of severe hyposmia or anosmia 


Evaluation of taste capacity 


Recommended in patients with taste dysfunction 




Evaluation of a patients' capacity to 
breathe through the nose 


* Anterior 

* Acoustic rhinometry 

Recommended parameter in clinical trials 

Helpful in clinical practise to evaluate the evolution of nasal 




Evaluation of NO levels in nasal cavity 

reaction of expired air 

Helpful as screening tool in PCD 


Collection of nasal mucosa/cells/ 
secretions for analysis 

* Nasal secretions 

* Nasal scraping 

* Nasal biopsy 


* nasal sampling in experimental/clinical studies 

* nasal secretions for B2 transferrin analysis in suspicion of 
CSF leak 

* biopsy in case of unilateral/malignant disease 


Evaluation of the sensitization state, 
immune system, endocrine system 
Evaluation of mucociliary function 
Evalution of chloride content in sweat 

* Blood test 

* MCT, nasal NO, EM, 
ciliogenesis in vitro 

* Sweat test 

Recommended as diagnostic tool in severe rhinitis, 
rhinosinusitis and nasal polyp disease with suspicion of 
underlying auto-immune, immunologic or ciliary disease 

Test-time: 35 min. 
Test-retest reliability: not found. 
Country: USA 
Smell diskettes test 

Method: A screening test of olfaction was designed 
[135] using 8 diskettes containing different odorants 
(coffee, vanilla, smoke, peach, pineapple, rose, coconut, 
vinegar). These diskettes (5x6 cm) are widely used in 
the perfume and flavour industry as applicators for 
odorants. The odorants were used in a high suprathres- 
hold concentration. The test was designed as a triple 
forced multiple choice test, resulting in a score from 0 

to 8 correct answers. The answers were presented on a 
questionnaire with illustrations. 

Test-time: 5 min. 

Test-retest reliability: r = 0.99 

Country: Zurich, Switzerland 
Odourant confusion matrix 

Method: Odorant identification test in which the number 
of correct odorant identifications quantifies the level of 
olfactory function [136]. The OCM reflects distortions of 
sensory perception as errors in identification. Subjects 
attempted to identify each of 10 odorant (ammonia, cin- 
namon, licorice, mint, mothballs, orange, rose, rubbing 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 33 of 39 

alcohol, vanilla, vinegar, vex) stimuli (plus a blank known 
as a vex) from a list of 10 odorant names, which was visi- 
ble at all times. Subjects were not told of the presence of 
the vex, and were asked to respond to all stimuli with an 
odor name chosen from the list of names. The 11 stimuli 
were given to the subject in 11 randomized blocks, 
resulting in a total of 121 stimulus presentations [136]. 

Test-time: 15 min. 

Test-retest reliability: not found. 

Country: USA 
Dutch odour identification test (GITU) 

Method: Identification of 18 or 36 odours in jars. Forced 
choice either from 4 alternatives or from a list of 24 for 
18 odours to identify [137]. 

Test-time: not found. 

Test-retest reliability: not found. 

Subject differences: 

Country: The Netherlands 
YN-odour Identification Test (YN-OIT) 

Methods: identification was assessed with a four alterna- 
tive-forced-choice task modified from the UPSIT odours 
and a yes/no task yielding measures of discrimination 
and response bias for the same stimulus material [138]. 

Test-time: not found 

Test-retest: not found 

Country: USA 
T&T Olfactometer 

Methods: The T&T olfactometer is the most commonly 
method used in patients suffering from smelling disor- 
ders. The T&T olfactometer (Daiichi-Yakuhin, Tokyo, 
Japan) consists of five test odorants [139]. Each odorant 
was diluted into eight log-step concentration series with 
either propylene glycol or liquid paraffin (grade 5 to -2). 
The detection threshold is the weakest concentration at 
which the stimulus is firstly noticed. The concentration 
at which a qualitative sensation is first recognized is 
recorded as the recognition threshold. 

Test-time: not found 

Test-retest: not found 

Country: Japan 
San Diego Odor Identification Test (SDOIT) 
Methods: Eight-item odour blind identification test [140] 
that uses common odours typically found in the home 
(chocolate, coffee, etc). Odorants were wrapped in gauze 
and kept in opaque containers to minimize visual clues. 
The inter-stimulus interval was 45 seconds to minimize 
adaptation. A picture board with illustrations of the tar- 
get items (8) as well as distracters (12) was presented to 
aid in identification. The odorants were presented in 
random order to the participant 

Test-time: not found 

Test-retest: r: 0.86 

Country: USA 

Cross-Cultural Smell Identification Test (CC-SIT) 

Methods: 12-item self-administered micro-encapsuled 
odour identification test, analogous to the UPSIT that 
incorporates multicultural odorant items selected from the 
UPSIT that are familiar to most persons from North 
America, European, South American, and Asian cultures 

Test-time: <5 min. 

Test-retest: r: 0.71 

Country: USA, Europe, Asia 
Combined olfactory test (COT) 

Robson et al. [142] creates the COT developed a screen- 
ing test to evaluate the olfaction in adults and children. 

Method: Threshold with n-butanol in plastic contain- 
ers, and identification of 9 odours in jars with forced 
choice with 4 options. 

Test-time: not found 

Test-retest reliability: not found 

Country: UK, New Zealand 
Sniff in' -Sticks 

Method: Test of nasal chemosensory performance based 
on pen-like odour dispensing devices [143]. For evaluation 
of odour sensation, the cap was removed by the clinician 
for 3 seconds and the pen's tip placed 2 cm from both 
nostrils. It comprises three tests of olfactory function, 
namely tests for odour threshold (n-butanol by means of a 
single staircase), odour discrimination (16 pairs of odor- 
ants, triple forced choice), and odour identification 
(16 common odorants, multiple forced choice from four 
verbal items per test odorant). Criteria for the selection of 
odorants were as follows: 1. subjects should be familiar 
with all odor-describing items used in the test; 2. odorants 
included in the test should be similar with regard to both 
intensity and hedonic tone; and 3. the successful identifi- 
cation of individual odorants from a list of four descriptors 
should be >75% in healthy subjects. 
Test-time: 25 min. 

Test-retest reliability: r: 0.61, r: 0.54, and r: 0.73 for 
threshold, discrimination, and identification respectively. 

Country: Germany, USA 
Candy smell test (CST) 

Method: an easy-to-use, reliable, and fast test of retrona- 
sal olfactory performance (23 aromatized sorbitol candies 
using a four-alternative with forced-choice procedure) 
suitable for the screening of smell function in children 
above the age of 6 years and adults [144]. 

Test-time: 5 minutes 

Test-retest reliability: r = 0.75. 

Country: Germany. 
Alcohol Sniff Test (AST) 

Method: In 1997, Davidson and Murphy developed a 
screening test to evaluate the olfaction in adults and 
children [145]. The AST is a rapidly administered and 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 34 of 39 

employs odour material readily available in the medical 
environment, providing a measure of first cranial nerve 
activity. A standard 70% isopropyl alcohol prep pad was 
opened such that 0.5 cm of the pad itself was visible. 
The alcohol pad was placed beneath the nostrils while 
the subject inspired to familiarize with the alcohol 
odour. Active sniffing and deep inspiration were dis- 
couraged. Then the alcohol pad was placer 30 cm below 
the nose and with each inspiration the pad is placed 
lcom closer to the nose until the subject detected the 
presence of the odour. The distance from the anterior 
nostrils to the alcohol was measured in cm. The proce- 
dure was repeated five times and the mean distance 
defined the threshold. 

Test-time: 5 minutes 

Test-retest reliability: r = 0.8. 

Country: USA 
Culturally Adjusted University of Pennsylvania Smell 
Identification Test (CA-UPSIT) 

Method: Ahlskog et al. developed a culturally adjusted 
olfactory test battery, derived from the original UPSIT 
for clinical use on the Chamorro inhabitants of Guam, a 
western Pacific island [146]. Identification of 20 microen- 
capsulated odours with the "scratch and sniff technique. 
Each of the 20 odours has four response alternatives. 
Target odours included: smoke, lilac, lemon, bubble gum, 
motor oil, banana, leather, coconut, onion, gasoline, pea- 
nut, dill pickle, lime, watermelon, grass, soap, cherry, 
strawberry, root beer, and mint. 

Test-time: not found 

Test-retest reliability: not found. 

Country: USA 
Kremer et al [147] 

Method: Olfactory test using spray bottles. The atomizer 
bottles were made of glass and contained 12.5 ml (10 g) 
of fluid. A special administration valve limited the 
amount of solution set free with each application to 
exactly 2 mg. The even distribution of the expelled solu- 
tion was assured by the extremely fine atomization pro- 
duced. The average size of the aerosol was 40 um. For 
hygienic reasons a replaceable valve was used. To imple- 
ment the olfactory test using spray bottles the patient 
was required to hold the atomizer 5 cm before an opened 
mouth. The spray was administered during inspiration, 
and afterwards the patient was asked to exhale through 
the nose, keeping the mouth closed. Alternatively, the 
solution colud be sprayed into the lid of the bottleand 
then be sniffed. Between separate applications the patient 
was given a rest period of at least 30 seconds. The sub- 
stances in the olfactory spray test were: rose, cinnamon, 
banana, pine essence, tangerine, and peppermint. The 
spray test was shown to be easily performed and was sui- 
table as a screening test, with a sensitivity of 88% and a 
specificity of 100%. 

Test-time: 4 minutes 

Test-retest reliability: not found 

Country: Germany, The Netherlands 
Scandinavian Odour-Identification Test (SOIT) 
Method: Nordin et al. [148] developed this olfactory test 
to address the need for a culturally valid odour-identifica- 
tion test for clinical use on the Scandinavian population 
that has good ability to generalize performance to olfac- 
tory status, assess olfactory and trigeminal function sepa- 
rately with a good sensitivity and specificity. 16 odours 
('pine needle, peppermint, juniper berry, violet, orange, 
cinnamon, lilac, apple, lemon, tar, anise, vanilla, bitter 
almond, clove, ammonia) to assess both cranial nerves. 
The stimulus order was randomize for each participant 
(>600). The liquid odorant was injected into a tampon 
filled to saturation and placed in an opaque, 80 ml glass 
jar. For each stimulus the participant was provided with a 
written list of four response alternatives from which to 
choose the most appropriate item for identification. The 
stimuli were presented birhinally, 5 cm under the nose, 
for as long as required to accomplish the task. 

Test-time: 15 minutes 

Test-retest reliability: r = 0.79. 

Country: Sweden, Finland 
Pocket Smell Test [56] 

Method: A screening measure of odour identification 
derived from the University of Pennsylvania Smell Identi- 
fication Test (UPSIT) with identification of 3 microen- 
capsulated odours with the "scratch and sniff technique. 
Each of the three PST tasks contains four response alter- 
natives [149]. Target odours included: smoke, lilac, and 
lemon. After releasing the odour, the examiner read the 
four response alternatives continuously until the patient 
responded. Patients were encouraged to guess if they 
were unsure. Nostrils were not tested separately. 

Sample size: 140 

Country: USA 
Eloit and Trotier Olfactory Test 

Methods: computed-assisted olfactory test to measure 
thresholds, detection, and identification using 5 odours: 
phenyl-ethyl-alcohol (PEA; flowers, rose, jasmine), cyclo- 
tene (CYC; caramel, cake), isovaleric acid (IVA; fruits, 
apricot, peach), undecalactone (UND; cowshed, slurry), 
and skatole (SKA; faecal). These chemically stable sub- 
stances in bottles evoke different odour notes. A software 
was developed to assist in the procedure of the experi- 
ment. At the beginning, participants get accustomed with 
the 5 odours at the highest concentration and learned to 
name them. Every odour was divided in 7 different des- 
cending concentrations. For each bottle, the subject was 
asked to decide whether it contained an odorant and, if 
so, which odorant was present. For each odorant, the 
detection level was taken as the highest concentration 
not perceived plus one. The identification level was taken 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 35 of 39 

as the smallest concentration correctly identified in a ser- 
ies of correct identification beginning with the highest 
concentration [150]. 

Test-time: not found 

Test-retest: not found 

Country: France 
Ramdon Test 

Method: a labelling of 16 concentrations of two odor- 
ants (citrus, rose) randomly presented for thresholds, 
discrimination, and identification [151]. Subjects were 
blindfolded to prevent visual identification of the odour- 
containing pens. 

Test-time: 10 minutes 

Test-retest reliability: r = 0.71. 

Country: Germany 
Four-minute odour identification test 

Method: Screening test on the basis of the odour identifi- 
cation test as used in the "Sniffin' Sticks" olfactory test 
[152]. Identification of 12 microencapsulated odours in 
pens. For odour presentation the cap is removed by the 
experimenter for approximately 3 seconds and the pen's 
tip is placed approximately 2 cm in front of both nostrils. 
Identification of individual odorants was performed from a 
list of 4 descriptors each. Target odours included: cinna- 
mon, banana, lemon, licorice, pineapple, coffe, cloves, rose, 
leather, fish, orange, and peppermint. Nostrils can be 
tested separately. 

Test-time: 4 minutes 

Test-retest reliability: r = 0.78. 

Country: Germany 
Barcelona Smell Test (BAST-24) 

Method: Olfactory test addressed to the need for a cultu- 
rally valid odour-identification test for clinical use on the 
Spanish population and in general for the Mediterranean 
countries. 24 odours, 20 odours (banana, gasoline, lemon, 
rose, onion, smoked, anise, coconut, vanilla, melon, man- 
darin, bitter almond, pineapple, cheese, strawberry, mush- 
room, eucalyptol, clove, turpentine, and peach) to assess 
the 1st cranial nerve and 4 odours (vinegar, formol, mus- 
tard, ammonia) to assess the 5th cranial nerve. Hermetic 
containers were designed to contain the different odorants 
in a semi-solid state. BAST-24 scores smell detection, 
identification, and forced choice. Nostrils can be tested 
separately, smell identification was scored slightly higher 
in the left than in the right nostril for both cranial nerve. 
BAST-24 was found to be a valid, reliable, and reproduci- 
ble test [153]. 

Test-time: 20 minutes. 

Test-retest reliability: 

Country: Spain 
Nez du Vin smell test 

Six odours initially derived from a kit used to educate 
wine tasters presented on paper strips with a forced 
choice between 4 possibilities. 

Time: 2 minutes 

Test retest -correlation with UPSIT: r = 0.79, p < 

0. 001 

Nez du Vin smell test 

Six odours initially derived from a kit used to educate 
wine tasters presented on paper strips with a forced 
choice between 4 possibilities [154]. Test-time: 2 min. 
Test retest -correlation with UPSIT: r = 0.79, p < 0.001. 


Consent for publication of photos was obtained from all 
pictured patients or their relatives. 


AR: Allergic rhinitis; ASNC: Allergen-specific nasal challenge test; CF: Cystic 
fibrosis; CRS: Chronic rhinosinusitis; CT scan: Computerized Tomography 
scan; MRI: Magnetic resonance imaging; NL: Nasal lavage; NO: Nitric oxicde; 
NP: Nasal polyps; PCD: Primay ciliary dyskinesia; PNIF: Peak nasal inspiratory 

Author details 

1 Royal National Throat, Nose and Ear Institute, London, UK. 2 University 
Hospitals Leuven, Belgium. 3 University Hospital Barcelona, Spain. 4 University 
Hospital Ghent, Belgium. 5 University Hospital Amsterdam, The Netherlands. 
6 University Hospital Rotterdam, The Netherlands. 'University Hospital Zagreb, 
Croatia. 8 University Hospital of Genoa, Italy. 'Center for Applied Genomics, 
Philadelphia, USA. 

Authors' contributions 

History of patient by GS; nasal clinical examination by PH; allergy tests and 
nasal provocation tests by GP; assessing the senses of smell and taste by JM, 
JG and IA; microbiology by LK; blood tests by GS; imaging in rhinology by 
LK and VL; evaluation of nasal patency, nasal peak flow, rhinomanometry, 
acoustic rhinometry by PH; quality of life assessment in rhinosinusitis, patient 
reported outcomes, rhinitis control tests by RGvW; nasal air sampling, NO 
measurement by GS; nasal cellular sampling, lavages, cytology, biopsies by 
PG and CB; evaluation of mucociliary transport by PH; diagnosis of 
occupational rhinitis by ET; future needs in clinical and research tools in 
rhinology by WF and CvD; concluding remarks and recommendations by GS 
and PH. All authors read and approved the final manuscript. 

Competing interests 

All authors declare they have no competing interests. 

Received: 12 May 2011 Accepted: 10 June 201 1 Published: 10 June 2011 


1. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al: 
Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in 
collaboration with the World Health Organization, GA(2)LEN and 
AllerGen). Allergy 2008, 63(Suppl 86):8-1 60. 

2. Fokkens W, Lund V, Mullol J: European position paper on rhinosinusitis 
and nasal polyps 2007. Rhino! Suppl 2007, , 20: 1-1 36. 

3. Williams PB, Ahlstedt S, Barnes JH, Soderstrom L, Portnoy J: Are our 
impressions of allergy test performances correct? Ann Allergy Asthma 
Immunol 2003, 91(1)26-33. 

4. Hellings PW, Fokkens WJ: Allergic rhinitis and its impact on 
otorhinolaryngology. Allergy 2006, 61(6):656-64. 

5. Bousquet J, Van Cauwenberge P, Khaltaev N: Allergic rhinitis and its 
impact on asthma. J Allergy Clin Immunol 2001, 108(5 Suppl):S1 47-334. 

6. Schipper H: Guidelines and caveats for quality of life measurement in 
clinical practice and research. Oncology (Williston Park) 1990, 4(5):51-7, 
discussion 70. 

Scadding ef al. Clinical and Translational Allergy 201 1, 1:2 

7. Petersen KD, Kronborg C, Gyrd-Hansen D, Dahl R, Larsen JN, Lowenstein H: 
Quality of life in rhinoconjunctivitis assessed with generic and disease- 
specific questionnaires. Allergy 2008, 63(3):284-91. 

8. Hurst JR, Wilkinson TM, Donaldson GC, Wedzicha JA: Upper airway 
symptoms and quality of life in chronic obstructive pulmonary disease 
(COPD). Respir Med 2004, 98(8):767-70. 

9. Passalacqua G, Pasquali M, Ariano R, Lombardi C, Giardini A, Baiardini I, et al: 
Randomized double-blind controlled study with sublingual 
carbamylated allergoid immunotherapy in mild rhinitis due to mites. 
Allergy 2006, 61(7):849-54. 

10. Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey 
(SF-36). I. Conceptual framework and item selection. Med Care 1992, 

11. Ware J Jr, Kosinski (VI, Keller SD: A 12-ltem Short-Form Health Survey: 
construction of scales and preliminary tests of reliability and validity. 

Med Care 1996, 34(3)220-33. 

12. Melzack R: The short-form McGill Pain Questionnaire. Pain 1987, 

1 3. Robinson K, Gatehouse S, Browning GG: Measuring patient benefit from 
otorhinolaryngological surgery and therapy. Ann Otol Rhinol Laryngol 
1996, 105(6):415-22. 

14. Juniper EF, Guyatt GH: Development and testing of a new measure of 
health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991, 

15. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN: Development and 
validation of the mini Rhinoconjunctivitis Quality of Life Questionnaire. 
Clin Exp Allergy 2000, 30(1 ):1 32-40. 

16. Juniper EF, Guyatt GH, Dolovich J: Assessment of quality of life in 
adolescents with allergic rhinoconjunctivitis: development and testing of 
a questionnaire for clinical trials. J Allergy Clin Immunol 1 994, 93(2):41 3-23. 

1 7. Benninger MS, Senior BA: The development of the Rhinosinusitis 
Disability Index. Arch Otolaryngol Head Neck Surg 1 997, 1 23(1 1 ):1 1 75-9. 

18. Piccirillo JF, Merritt MG Jr, Richards ML: Psychometric and clinimetric 
validity of the 20-ltem Sino-Nasal Outcome Test (SNOT-20). Otolaryngol 
Head Neck Surg 2002, 126(1 ):41-7. 

19. Hurst NP, Jobanputra P, Hunter M, Lambert M, Lochhead A, Brown H: 
Validity of Euroqol-a generic health status instrument-in patients with 
rheumatoid arthritis. Economic and Health Outcomes Research Group. Br 
J Rheumatol 1994, 33(7):655-62. 

20. Revicki DA, Leidy NK, Brennan-Diemer F, Thompson C, Togias A: 
Development and preliminary validation of the multiattribute Rhinitis 
Symptom Utility Index. Qual Life Res 1 998, 7(8):693-702. 

21. van Oene CM, van Reij EJ, Sprangers MA, Fokkens WJ: Quality-assessment 
of disease-specific quality of life questionnaires for rhinitis and 
rhinosinusitis: a systematic review. Allergy 2007, 62(1 2):1 359-71. 

22. Baiardini I, Pasquali M, Giardini A, Specchia C, Passalacqua G, Venturi S, et al 
Rhinasthma: a new specific QoL questionnaire for patients with rhinitis 
and asthma. Allergy 2003, 58(4)289-94. 

23. Sintonen H: The 15D instrument of health-related quality of life: 
properties and applications. Ann Med 2001, 33(5):328-36. 

24. Juniper EF, Rohrbaugh T, Meltzer EO: A questionnaire to measure quality 
of life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin 
Immunol 2003, 1 1 1 (3):484-90. 

25. Verdalle P, Roquet E, Hor F, Raynal M, Courtois A, Bauduceau B, et al 
Pituitary abscess. A rare complication of sinusitis. Rev Laryngol Otol Rhinol 
(Bord) 1997, 118(5)327-9. 

26. Landgraf JM, Maunsell E, Speechley KN, Bullinger M, Campbell S, Abetz L, 
et al: Canadian-French, German and UK versions of the Child Health 
Questionnaire: methodology and preliminary item scaling results. Qual 
Life Res 1998, 7(5):433-45. 

27. Kay DJ, Rosenfeld RM: Quality of life for children with persistent sinonasal 
symptoms. Otolaryngol Head Neck Surg 2003, 1 28(1 ):1 7-26. 

28. Anderson ER, Murphy MP, Weymuller EA Jr: Clinimetric evaluation of the 
Sinonasal Outcome Test-16. Student Research Award 1998. Otolaryngol 
Head Neck Surg 1999, 121(6):702-7. 

29. Gliklich RE, Hilinski JM: Longitudinal sensitivity of generic and specific 
health measures in chronic sinusitis. Qual Life Res 1995, 4(1)27-32. 

30. Atlas SJ, Gallagher PM, Wu YA, Singer DE, Gliklich RE, Metson RB, et al: 
Development and validation of a new health-related quality of life 
instrument for patients with sinusitis. Qual Life Res 2005, 14(5):1 375-86. 

Page 36 of 39 

31. Nathan RA, Santilli J, Rockwell W, Glassheim J: Effectiveness of 
immunotherapy for recurring sinusitis associated with allergic rhinitis as 
assessed by the Sinusitis Outcomes Questionnaire. Ann Allergy Asthma 
Immunol 2004, 92(6):668-72. 

32. Rosbe KW, Jones KR: Usefulness of patient symptoms and nasal 
endoscopy in the diagnosis of chronic sinusitis. Am J Rhinol 1998, 

33. Johansson L, Akerlund A, Holmberg K, Melen I, Stierna P, Bende M: 
Evaluation of methods for endoscopic staging of nasal polyposis. Acta 
Otolaryngol 2000, 120(1):72-6. 

34. Feldmann H: History of diaphanoscopy. Pictures from the history of 
otorhinolaryngology, illustrated by instruments from the collection of 
the Ingolstadt German Medical History Museum. Laryngorhinootologie 
1998, 77(5)297-304. 

35. Midwinter Kl, Ahmed A, Willatt D: A randomised trial of flexible versus 
rigid nasendoscopy in outpatient sinonasal examination. Clin Otolaryngol 
Allied Sci 2001, 26(4)281-3. 

36. Kerkhof M, Droste JH, de Monchy JG, Schouten JP, Rijcken B: Distribution 
of total serum IgE and specific IgE to common aeroallergens by sex and 
age, and their relationship to each other in a random sample of the 
Dutch general population aged 20-70 years. Dutch ECRHS Group, 
European Community Respiratory Health Study. Allergy 1996, 

37. Nelson HS, Rosloniec DM, McCall LI, Ikle D: Comparative performance of 
five commercial prick skin test devices. J Allergy Clin Immunol 1993, 

38. Engler DB, DeJarnatt AC, Sim TC, Lee JL, Grant JA: Comparison of the 
sensitivity and precision of four skin test devices. J Allergy Clin Immunol 
1992, 90(6 Pt 1)385-91. 

39. Williams AJ, Baghat MS, Stableforth DE, Cayton RM, Shenoi PM, Skinner C: 
Dysphonia caused by inhaled steroids: recognition of a characteristic 
laryngeal abnormality. Thorax 1983, 38(11):813-21. 

40. Bilo BM, RuefF F, Mosbech H, Bonifazi F, Oude-Elberink JN: Diagnosis of 
Hymenoptera venom allergy. Allergy 2005, 60(1 1 ):1 339-49. 

41. Devillers AC, de Waard-van der Spek FB, Mulder PG, Oranje AP: Atopy 
patch tests with aeroallergens in children aged 0-3 years with atopic 
dermatitis. Allergy 2008, 63(8):1 088-90. 

42. Crimi E, Gaffi D, Frittoli E, Borgonovo B, Burastero SE: Depletion of 
circulating allergen-specific Th2 T lymphocytes after allergen exposure 
in asthma. J Allergy Clin Immunol 1997, 99:788-97. 

43. Chinoy B, Yee E, Bahna SL: Skin testing versus radioallergosorbent testing 
for indoor allergens. Clin Mol Allergy 2005, 3(1):4. 

44. Powe DG, Jagger C, Kleinjan A, Carney AS, Jenkins D, Jones NS: 'Entopy': 
localized mucosal allergic disease in the absence of systemic responses 
for atopy. Clin Exp Allergy 2003, 33(1 0):1 374-9. 

45. Rondon C, Romero JJ, Lopez S, Antunez C, Martin-Casanez E, Torres MJ, 
ef al: Local IgE production and positive nasal provocation test in 
patients with persistent nonallergic rhinitis. J Allergy Clin Immunol 2007, 

46. Melillo G, Bonini S, Cocco G, Davies RJ, de Monchy JG, Frolund L, ef al: 
EAACI provocation tests with allergens. Report prepared by the 
European Academy of Allergology and Clinical Immunology 
Subcommittee on provocation tests with allergens. Allergy 1997, 52(35 

47. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczynska M, 
Picado C, Scadding G, et al: EAACI/GA2LEN guideline: aspirin provocation 
tests for diagnosis of aspirin hypersensitivity. Allergy 2007, 62(1 0):1 1 11-8. 

48. Milewski M, Mastalerz L, Nizankowska E, Szczeklik A: Nasal provocation test 
with lysine-aspirin for diagnosis of aspirin-sensitive asthma. J Allergy Clin 
Immunol 1998, 101(5)581-6. 

49. Gerth van Wijk R, Dieges PH: Nasal reactivity to histamine and 
methacholine: two different forms of upper airway responsiveness. 
Rhinology 1994, 32(3):1 1 9-22. 

50. Larivee Y, Leon Z, Salas-Prato M, Ganeva E, Desrosiers M: Evaluation of the 
nasal response to histamine provocation with acoustic rhinometry. J 
Otolaryngol 2001, 30(6)319-23. 

51. Braat JP, Mulder PG, Fokkens WJ, van Wijk RG, Rijntjes E: Intranasal cold dry 
air is superior to histamine challenge in determining the presence and 
degree of nasal hyperreactivity in nonallergic noninfectious perennial 
rhinitis. Am J Respir Crit Care Med 1998, 157(6 Pt 1):1 748-55. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

52. Wilson AM, Sims EJ, Orr LC, Robb F, Lipworth BJ: An evaluation of short- 
term corticosteroid response in perennial allergic rhinitis using 
histamine and adenosine monophosphate nasal challenge. Br J Clin 
Pharmacol 2003, 55(4):354-9. 

53. Vaidyanathan S, Nair A, Barnes ML, Meldrum K, Lipworth BJ: Effect of 
levocetirizine on nasal provocation testing with adenosine 
monophosphate compared with allergen challenge in allergic rhinitis. 
Clin Exp Allergy 2009, 39(3):409-16. 

54. Sanico AM, Atsuta S, Proud D, Togias A: Dose-dependent effects of 
capsaicin nasal challenge: in vivo evidence of human airway neurogenic 
inflammation. J Allergy Clin Immunol 1997, 100(51:632-41. 

55. Cruz AA, Togias A: Upper airways reactions to cold air. Curr Allergy Asthma 
Rep 2008, 8(2):111-7. 

56. Zinreich SJ, Kennedy DW, Malat J, Curtin HD, Epstein Jl, Huff LC, et al: 
Fungal sinusitis: diagnosis with CT and MR imaging. Radiology 1988, 

57. Klimacka-Nawrot E, Suchecka W: Methods of taste sensitivity examination. 
Wiad Lek 2008, 61(7-9):207-10. 

58. Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the 
biological activity of endothelium-derived relaxing factor. Nature 1987, 

59. Coleman JW: Nitric oxide in immunity and inflammation, frit 
Immunopharmacol 2001, 1(8): 1397-406. 

60. Alving K, Weitzberg E, Lundberg JM: Increased amount of nitric oxide in 
exhaled air of asthmatics. Eur Respir J 1 993, 6(9):1 368-70. 

61. Kawamoto H, Takumida M, Takeno S, Watanabe H, Fukushima N, Yajin K: 
Localization of nitric oxide synthase in human nasal mucosa with nasal 
allergy. Acta Otolaryngol Suppl 1998, 539:65-70. 

62. Lundberg JO, Weitzberg E, Rinder J, Rudehill A, Jansson O, Wiklund NP, 
et al: Calcium-independent and steroid-resistant nitric oxide synthase 
activity in human paranasal sinus mucosa. Eur Respir J 1996, 

9(7): 1 344-7. 

63. ATS/ERS recommendations for standardized procedures for the online 
and offline measurement of exhaled lower respiratory nitric oxide and 
nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005, 171(8):912-30. 

64. Bartley J, Fergusson W, Moody A, Wells AU, Kolbe J: Normal adult values, 
diurnal variation, and repeatability of nasal nitric oxide measurement. 
AmJRhinol 1999, 13(5)401-5. 

65. Parikh A, Scadding GK, Gray P, Belvisi MG, Mitchell JA: High levels of nitric 
oxide synthase activity are associated with nasal polyp tissue from 
aspirin-sensitive asthmatics. Acta Otolaryngol 2002, 122(3):302-5. 

66. Ragab SM, Lund VJ, Saleh HA, Scadding G: Nasal nitric oxide in objective 
evaluation of chronic rhinosinusitis therapy. Allergy 2006, 61 (6):71 7-24. 

67. Delclaux C, Malinvaud D, Chevalier-Bidaud B, Callens E, Mahut B, Bonfils P: 
Nitric oxide evaluation in upper and lower respiratory tracts in nasal 
polyposis. Clin Exp Allergy 2008, 38(7)1 140-7. 

68. Raza T, Elsherif HS, Zulianello L, Plouin-Gaudon I, Landis BN, Lacroix JS: 
Nasal lavage with sodium hypochlorite solution in Staphylococcus 
aureus persistent rhinosinusitis. Rhinology 2008, 46(1 ):1 5-22. 

69. Weitzberg E, Lundberg JO: Humming greatly increases nasal nitric oxide. 
Am J Respir Crit Care Med 2002, 166(2):144-5. 

70. Watelet JB, Gevaert P, Holtappels G, Van Cauwenberge P, Bachert C: 
Collection of nasal secretions for immunological analysis. Eur Arch 
Otorhinolaryngol 2004, 261(5)242-6. 

71. Knowles GK Townsend P, Turner-Warwick M: A standardized filter paper 
technigue for assessing nasal secretory activity. Clin Allergy 1981, 

72. Naclerio RM, Baroody FM: Response of nasal mucosa to histamine or 
methacholine challenge: use of a quantitative method to examine the 
modulatory effects of atropine and ipratropium bromide. J Allergy Clin 
Immunol 1992, 90(6 Pt 2):1 051-4. 

73. Biewenga J, Stoop AE, Baker HE, Swart SJ, Nauta JJ, van Kamp GJ, et al: 
Nasal secretions from patients with polyps and healthy individuals, 
collected with a new aspiration system: evaluation of total protein and 
immunoglobulin concentrations. Ann Clin Biochem 1991, 28(Pt 3)260-6. 

74. Pipkorn U, Karlsson G, Enerback L: A brush method to harvest cells from 
the nasal mucosa for microscopic and biochemical analysis. J Immunol 
Methods 1988, 112(1)37-42. 

75. van Benten LI, van Drunen CM, Koopman LP, van Middelkoop BC, Hop WC, 
Osterhaus AD, et al: Age- and infection-related maturation of the nasal 
immune response in 0-2-year-old children. Allergy 2005, 60(2)226-32. 

Page 37 of 39 

76. Meltzer EO, Orgel HA, Rogenes PR, Field EA: Nasal cytology in patients 
with allergic rhinitis: effects of intranasal fluticasone propionate. J Allergy 
Clin Immunol 1994, 94(4):708-15. 

77. Jalowayski AA, Walpita P, Puryear BA, Connor JD: Rapid detection of 
respiratory syncytial virus in nasopharyngeal specimens obtained with 
the rhinoprobe scraper. J Clin Microbiol 1990, 28(4):738-41 . 

78. Fokkens WJ, Vroom TM, Gerritsma V, Rijntjes E: A biopsy method to obtain 
high quality specimens of nasal mucosa. Rhinology 1988, 26(4)293-5. 

79. KleinJan A, McEuen AR, Dijkstra MD, Buckley MG, Walls AF, Fokkens WJ: 
Basophil and eosinophil accumulation and mast cell degranulation in 
the nasal mucosa of patients with hay fever after local allergen 
provocation. J Allergy Clin Immunol 2000, 106(4):677-86. 

80. Fokkens WJ, Holm AF, Rijntjes E, Mulder PG, Vroom TM: Characterization 
and quantification of cellular infiltrates in nasal mucosa of patients with 
grass pollen allergy, non-allergic patients with nasal polyps and controls. 
Int Arch Allergy Appl Immunol 1990, 93(1)66-72. 

81. Howarth PH, Persson CG, Meltzer EO, Jacobson MR, Durham SR, Silkoff PE: 
Objective monitoring of nasal airway inflammation in rhinitis. J Allergy 
Clin Immunol 2005, 115(3 Suppl 1)5414-41. 

82. Juliusson S, Pipkorn U, Karlsson G, Enerback L: Mast cells and eosinophils 
in the allergic mucosal response to allergen challenge: changes in 
distribution and signs of activation in relation to symptoms. J Allergy Clin 
Immunol 1992, 90(6 Pt 1):898-909. 

83. Jacobson MR, Juliusson S, Lowhagen O, Balder B, Kay AB, Durham SR: Effect 
of topical corticosteroids on seasonal increases in epithelial eosinophils 
and mast cells in allergic rhinitis: a comparison of nasal brush and 
biopsy methods. Clin Exp Allergy 1999, 29(10)1 347-55. 

84. Godthelp T, Holm AF, Fokkens WJ, Doornenbal P, Mulder PG, Hoefsmit EC, 
ef al: Dynamics of nasal eosinophils in response to a nonnatural allergen 
challenge in patients with allergic rhinitis and control subjects: a biopsy 
and brush study. J Allergy Clin Immunol 1996, 97(3):800-l 1. 

85. Nathan RA, Eccles R, Howarth PH, Steinsvag SK, Togias A: Objective 
monitoring of nasal patency and nasal physiology in rhinitis. J Allergy 
Clin Immunol 2005, 115(3 Suppl 1)5442-59. 

86. Fairley JW, Durham LH, Ell SR: Correlation of subjective sensation of nasal 
patency with nasal inspiratory peak flow rate. Clin Otolaryngol Allied So' 
1993, 18(1 ):1 9-22. 

87. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ: Subjective and objective 
markers of treatment response in patients with seasonal allergic rhinitis. 
Ann Allergy Asthma Immunol 2000, 85(2):1 1 1-4. 

88. Panagou P, Loukides S, Tsipra S, Syrigou K, Anastasakis C, Kalogeropoulos N: 
Evaluation of nasal patency: comparison of patient and clinician 
assessments with rhinomanometry. Acta Otolaryngol 1998, 1 1 8(6) 847-51. 

89. Jones AS, Viani L, Phillips D, Charters P: The objective assessment of nasal 
patency. Clin Otolaryngol Allied Sci 1991, 16(2)206-11. 

90. Morrissey MS, Alun-Jones T, Hill J: The relationship of peak inspiratory 
airflow to subjective airflow in the nose. Clin Otolaryngol Allied Sci 1990, 

91 . Eccles R, Jawad MS, Jawad SS, Angello JT, Druce HM: Efficacy and safety of 
single and multiple doses of pseudoephedrine in the treatment of nasal 
congestion associated with common cold. Am J Rhinol 2005, 19(1)25-31. 

92. Kiroglu AF, Bayrakli H, Yuca K, Cankaya H, Kiris M: Nasal obstruction as a 
common side-effect of sildenafil citrate. Tohoku J Exp Med 2006, 

93. Larsson C, Millqvist E, Bende M: Relationship between subjective nasal 
stuffiness and nasal patency measured by acoustic rhinometry. Am J 
Rhinol 2001, 15(6)403-5. 

94. Gungor A, Moinuddin R, Nelson RH, Corey JP: Detection of the nasal cycle 
with acoustic rhinometry: techniques and applications. Otolaryngol Head 
Neck Surg 1999, 120(2)238-47. 

95. Greenberg D, Broides A, Blancovich I, Peled N, Givon-Lavi N, Dagan R: 
Relative importance of nasopharyngeal versus oropharyngeal sampling 
for isolation of Streptococcus pneumoniae and Haemophilus influenzae 
from healthy and sick individuals varies with age. J Clin Microbiol 2004, 

96. Wald ER: Microbiology of acute and chronic sinusitis in children and 
adults. Am J Med Sci 1998, 316(1 ):1 3-20. 

97. Benninger MS, Payne SC, Ferguson BJ, Hadley JA, Ahmad N: Endoscopically 
directed middle meatal cultures versus maxillary sinus taps in acute 
bacterial maxillary rhinosinusitis: a meta-analysis. Otolaryngol Head Neck 
Surg 2006, 134(1)5-9. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 38 of 39 

98. Cohen M, Kofonow J, Nayak JV, Palmer JN, Chiu AG, Leid JG, et al: 
Biofilms in chronic rhinosinusitis: a review. Am J Rhino! Allergy 2009, 

99. Robinson S, Der-Haroutian V, Grove D, Rees G, Wormald PJ: Prevalence 
of pus in radiologically diseased sinuses in patients undergoing 
surgery for chronic rhinosinusitis. Otolaryngol Head Neck Surg 2005, 

100. Paju S, Bernstein JM, Haase EM, Scannapieco FA: Molecular analysis of 
bacterial flora associated with chronically inflamed maxillary sinuses. J 
Med Microbiol 2003, 52(Pt 7)591-7. 

101. Storm van's Gravesande K, Omran H: Primary ciliary dyskinesia: clinical 
presentation, diagnosis and genetics. Ann Med 2005, 37(6)439-49. 

102. Cohen NA: Sinonasal mucociliary clearance in health and disease. Ann 
Otol Rhinol Laryngol Suppl 2006, 196:20-6. 

103. Agu RU, Jorissen M, Willems T, Augustijns P, Kinget R, Verbeke N: In-vitro 
nasal drug delivery studies: comparison of derivatised, fibrillar and 
polymerised collagen matrix-based human nasal primary culture 
systems for nasal drug delivery studies. J Pharm Pharmacol 2001, 

104. Fuchs HA, Tanner SB: Granulomatous disorders of the nose and paranasal 
sinuses. Curr Opin Otolaryngol Head Neck Surg 2009, 17(1):23-7. 

105. Burbelo PD, Ching KH, Issa AT, Loftus CM, Li Y, Satoh M, et al: Rapid 
Serological Detection of Autoantibodies Associated with Sjogren's 
Syndrome. J Transl Med 2009, 7(1 ):83. 

106. Abuabara A: Cerebrospinal fluid rhinorrhoea: diagnosis and 
management. Med Oral Patol Oral Or Bucal 2007, 12(5):E397-400. 

107. Herbort CP, Rao NA, Mochizuki M: International criteria for the diagnosis 
of ocular sarcoidosis: results of the first International Workshop On 
Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm 2009, 17(3):160-9. 

108. Sinico RA, Di Toma L, Maggiore U, Bottero P, Radice A, Tosoni C, et al: 
Prevalence and clinical significance of antineutrophil cytoplasmic 
antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005, 

109. Sebastiani GD: Antineutrophil cytoplasmic antibodies. Reumatismo 2009, 

HO. Ng KP, Isenberg DA: Sjogren's syndrome: diagnosis and therapeutic 
challenges in the elderly. Drugs Aging 2008, 25(1):19-33. 

111. Bavbek S, Dursun AB, Birben E, Kalayci 0, Misirligil Z: Cellular allergen 
stimulation test with acetylsalicylic acid-lysine is not a useful test to 
discriminate between asthmatic patients with and without acetylsalicylic 
acid sensitivity. Int Arch Allergy Immunol 2009, 149(1)58-64. 

1 12. Fokkens WJ, Ebbens F, van Drunen CM: Fungus: a role in pathophysiology 
of chronic rhinosinusitis, disease modifier, a treatment target, or no role 
at all? Immunol Allergy Clin North Am 2009, 29(4):677-88. 

1 13. Scadding G, Scadding GK: Update on the use of nitric oxide as a 
noninvasive measure of airways inflammation. Rhinology 2009, 
47(2): 115-20. 

1 14. Jorissen M, Willems T, Van der Schueren B, Verbeken E, De Boeck K 
Ultrastructural expression of primary ciliary dyskinesia after ciliogenesis 
in culture. Acta Otorhinolaryngol Belg 2000, 54(3)343-56. 

1 15. Jorissen M, Willems T, Van der Schueren B: Ciliary function analysis for the 
diagnosis of primary ciliary dyskinesia: advantages of ciliogenesis in 
culture. Acta Otolaryngol 2000, 120(2)291-5. 

1 16. Voter KZ, Ren CL: Diagnosis of cystic fibrosis. Clin Rev Allergy Immunol 
2008, 35(3):100-6. 

117. Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D, et al: The cytotoxic 
T lymphocyte antigen-4 is a major Graves' disease locus. Hum Mol Genet 
1999, 8(7): 1195-9. 

1 18. Stankiewicz JA, Chow JM: Nasal endoscopy and the definition and 
diagnosis of chronic rhinosinusitis. Otolaryngol Head Neck Surg 2002, 

1 19. Bhattacharyya N, Fried MP: The accuracy of computed tomography in the 
diagnosis of chronic rhinosinusitis. Laryngoscope 2003, 11 3(1 ):1 25-9. 

1 20. Ashraf N, Bhattacharyya N: Determination of the "incidental" Lund score 
for the staging of chronic rhinosinusitis. Otolaryngol Head Neck Surg 2001, 

121. Varonen H, Savolainen S, Kunnamo I, Heikkinen R, Revonta M: Acute 
rhinosinusitis in primary care: a comparison of symptoms, signs, 
ultrasound, and radiography. Rhinology 2003, 41(1)37-43. 

122. Moscato G, Siracusa A: Rhinitis guidelines and implications for 
occupational rhinitis. Curr Opin Allergy Clin Immunol 2009, 9(2):1 10-5. 

123. Airaksinen L, Tuomi T, Vanhanen M, Voutilainen R, Toskala E: Use of nasal 
provocation test in the diagnostics of occupational rhinitis. Rhinology 

2007, 45(1)40-6. 

124. Castano R, Gautrin D, Theriault G, Trudeau C, Ghezzo H, Malo JL: 
Occupational rhinitis in workers investigated for occupational asthma. 
Thorax 2009, 64(1)50-4. 

125. Airaksinen LK, Tuomi TO, Tuppurainen MO, Lauerma Al, Toskala EM: 
Inhalation challenge test in the diagnosis of occupational rhinitis. Am J 
Rhinol 2008, 22(1)38-46. 

126. Moscato G, Pignatti P, Yacoub MR, Romano C, Spezia S, Perfetti L: 
Occupational asthma and occupational rhinitis in hairdressers. Chest 
2005, 128(5)3590-8. 

127. McArthur JG, Raulet DH: CD28-induced costimulation of T helper type 2 
cells mediated by induction of responsiveness to interleukin 4. J Exp 
Med 1993, 178(5)4 645-53. 

128. Clement PA, Gordts F: Consensus report on acoustic rhinometry and 
rhinomanometry. Rhinology 2005, 43(3):1 69-79. 

129. Pirila T, Nuutinen J: Acoustic rhinometry, rhinomanometry and the 
amount of nasal secretion in the clinical monitoring of the nasal 
provocation test. Clin Exp Allergy 1 998, 28(4)468-77. 

130. van Drunen CM, Vroling AB, Rinia AB, Fokkens WJ: Considerations on the 
application of microarray analysis in rhinology. Rhinology 2008, 

131. Vroling AB, Jonker MJ, Luiten S, Breit TM, Fokkens WJ, van Drunen CM: 
Primary nasal epithelium exposed to house dust mite extract shows 
activated expression in allergic individuals. Am J Respir Cell Mol Biol 2008, 


132. Vroling AB, Jonker MJ, Breit TM, Fokkens WJ, van Drunen CM: Comparison 
of expression profiles induced by dust mite in airway epithelia reveals a 
common pathway. Allergy 2008, 63(4)461-7. 

133. Doty RL, Shaman P, Dann M: Development of the University of 
Pennsylvania Smell Identification Test: a standardized 
microencapsulated test of olfactory function. Physiol Behav 1984, 

134. Cain WS, Gent J, Catalanotto FA, Goodspeed RB: Clinical evaluation of 
olfaction. Am J Otolaryngol 1983, 4(4):252-6. 

135. Briner HR, Simmen D: Smell diskettes as screening test of olfaction. 
Rhinology 1999, 37(4)445-8. 

136. Wright HN: Characterization of olfactory dysfunction. Arch Otolaryngol 
Head Neck Surg 1987, 113(2)463-8. 

137. Hendriks AP: Olfactory dysfunction. Rhinology 1988, 26(4):229-51 . 

138. Corwin J: Olfactory identification in hemodialysis: acute and chronic 
effects on discrimination and response bias. Neuropsychologia 1989, 

139. Takagi SF: A standardized olfactometer in Japan. A review over ten 
years. Ann N Y Acad Sci 1 987, 5 1 0:1 1 3-8. 

140. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM: 
Prevalence of olfactory impairment in older adults. Jama 2002, 

141. Doty RL, McKeown DA, Lee WW, Shaman P: A study of the test-retest 
reliability of ten olfactory tests. Chem Senses 1995, 20(6):645-56. 

142. Robson AK, Woollons AC, Ryan J, Horrocks C, Williams S, Dawes PJ: 
Validation of the combined olfactory test. Clin Otolaryngol Allied Sci 1996, 

143. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G: 'Sniffin' sticks': olfactory 
performance assessed by the combined testing of odor identification, 
odor discrimination and olfactory threshold. Chem Senses 1997, 

144. Renner B, Mueller CA, Dreier J, Faulhaber S, Rascher W, Kobal G: The candy 
smell test: a new test for retronasal olfactory performance. Laryngoscope 
2009, 119(3)487-95. 

145. Davidson TM, Murphy C: Rapid clinical evaluation of anosmia. The alcohol 
sniff test. Arch Otolaryngol Head Neck Surg 1997, 123(6)591-4. 

146. Ahlskog JE, Waring SC, Petersen RC, Esteban-Santillan C, Craig UK, 
O'Brien PC, et al: Olfactory dysfunction in Guamanian ALS, parkinsonism, 
and dementia. Neurology 1998, 51(6)4672-7. 

147. Kremer B, Klimek L, Mosges R: Clinical validation of a new olfactory test. 
Eur Arch Otorhinolaryngol 1998, 255(7)355-8. 

148. Nordin S, Bramerson A, Liden E, Bende M: The Scandinavian Odor- 
Identification Test: development, reliability, validity and normative data. 
Acta Otolaryngol 1998, 118(2)226-34. 

Scadding et al. Clinical and Translational Allergy 201 1, 1:2 

Page 39 of 39 

1 49. Solomon GS, Petrie WM, Hart JR, Brackin HB Jr: Olfactory dysfunction 
discriminates Alzheimer's dementia from major depression. J 
Neuropsychiatry Clin Neurosci 1998, 10(l):64-7, Winter. 

1 50. Trotier D, Bensimon JL, Herman P, Tran Ba Huy P, Doving KB, Eloit 0 
Inflammatory obstruction of the olfactory clefts and olfactory loss in 
humans: a new syndrome? Chem Senses 2007, 32(3):285-92. 

151. Kobal G, Palisch K, Wolf SR, Meyer ED, Huttenbrink KB, Roscher S, era/: A 
threshold-like measure for the assessment of olfactory sensitivity: the 
"random" procedure. Eur Arch Otorhinolaryngol 2001, 258(4): 168-72. 

1 52. Hummel T, Konnerth CG, Rosenheim K, Kobal G: Screening of olfactory 
function with a four-minute odor identification test: reliability, normative 
data, and investigations in patients with olfactory loss. Ann Otol Rhinol 
Laryngol 2001, 110(10)576-81. 

153. Guilemany JM, Garcia-Pinero A, Alobid I, Cardelus S, Centellas S, Bartra J, 
ef al: Persistent allergic rhinitis has a moderate impact on the sense of 
smell, depending on both nasal congestion and inflammation. 
Laryngoscope 2009, 119(2)233-8. 

154. McMahon C, Scadding GK: Le Nez du Vin-a quick test of olfaction. Clin 
Otolaryngol Allied Sci 1996, 21(3):278-80. 

doi:10.1 186/2045-7022-1-2 

Cite this article as: Scadding et al:. Diagnostic tools in Rhinology EAACI 
position paper. Clinical and Translational Allergy 201 1 1:2. 

Submit your next manuscript to BioMed Central 
and take full advantage of: 

• Convenient online submission 

• Thorough peer review 

• No space constraints or color figure charges 

• Immediate publication on acceptance 

• Inclusion in PubMed, CAS, Scopus and Google Scholar 

• Research which is freely available for redistribution 

Submit your manuscript at f\ RioM _-| rpntr ,i \ J •*"»■»•«• central